Bicyclic dihydroimidazolone cgrp receptor antagonists

ABSTRACT

Compounds of formula (I): wherein variables B, G 1 , G 2 , G 3 , G 4 , E a , E b , E c , A 1 , A 2 , A 3 , A 4 , R 6  and R PG  and Y are as described herein, which are antagonists of CGRP receptors and which are useful in the treatment or prevention of diseases in which the CGRP is involved, such as migraine. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.

BACKGROUND OF THE INVENTION

CORP (Calcitonin Gene-Related Peptide) is a naturally occurring 37-aminoacid peptide that is generated by tissue-specific alternate processingof calcitonin messenger RNA and is widely distributed in the central andperipheral nervous system. CGRP is localized predominantly in sensoryafferent and central neurons and mediates several biological actions,including vasodilation. CGRP is expressed in alpha- and beta-forms thatvary by one and three amino acids in the rat and human, respectively.CGRP-alpha and CGRP-beta display similar biological properties. Whenreleased from the cell, CGRP initiates its biological responses bybinding to specific cell surface receptors that are predominantlycoupled to the activation of adenylyl cyclase. CGRP receptors have beenidentified and pharmacologically evaluated in several tissues and cells,including those of brain, cardiovascular, endothelial, and smooth muscleorigin.

Based on pharmacological properties, these receptors are divided into atleast two subtypes, denoted CGRP₁ and CGRP₂. Human α-CORP-(8-37), afragment of CGRP that lacks seven N-terminal amino acid residues, is aselective antagonist of CGRP₁, whereas the linear analogue of CGRP,diacetoamido methyl cysteine CGRP ([Cys(ACM)2,7]CGRP), is a selectiveagonist of CGRP₂. CGRP is a potent neuromodulator that has beenimplicated in the pathology of cerebrovascular disorders such asmigraine and cluster headache. In clinical studies, elevated levels ofCGRP in the jugular vein were found to occur during migraine attacks(Goadsby et al., Ann. Neurol., 1990, 28, 183-187), and salivary levelsof CORP were shown to be elevated in migraine subjects between attacks(Bellamy et al., Headache, 2006, 46, 24-33). CGRP itself has been shownto trigger migrainous headache (Lassen et al., Cephalalgia, 2002, 22,54-61). In clinical trials, the CGRP antagonist BIBN4096BS has beenshown to be effective in treating acute attacks of migraine (Olesen etal., New Engl. J. Med., 2004, 350, 1104-1110) and was able to preventheadache induced by CGRP infusion in a control group (Petersen et al.,Clin. Pharmacol. Ther., 2005, 77, 202-213).

CORP-mediated activation of the trigeminovascular system may play a keyrole in migraine pathogenesis. Additionally, CGRP activates receptors onthe smooth muscle of intracranial vessels, leading to increasedvasodilation, which is thought to contribute to headache pain duringmigraine attacks (Lance, Headache Pathogenesis: Monoamines,Neuropeptides, Purines and Nitric Oxide, Lippincott-Raven Publishers,1997, 3-9). The middle meningeal artery, the principle artery in thedura mater, is innervated by sensory fibers from the trigeminal ganglionwhich contain several neuropeptides, including CGRP. Trigeminal ganglionstimulation in the cat resulted in increased levels of CGRP, and inhumans, activation of the trigeminal system caused facial flushing andincreased levels of CGRP in the external jugular vein (Goadsby et al.,Ann. Neurol., 1988, 23, 193-196). Electrical stimulation of the duramater in rats increased the diameter of the middle meningeal artery, aneffect that was blocked by prior administration of CORP(8-37), a peptideCGRP antagonist (Williamson et al., Cephalalgia, 1997, 17, 525-531).Trigeminal ganglion stimulation increased facial blood flow in the rat,which was inhibited by CGRP(8-37) (Escott et al., Brain Res. 1995, 669,93-99). Electrical stimulation of the trigeminal ganglion in marmosetproduced an increase in facial blood flow that could be blocked by thenon-peptide CORP antagonist BIBN4096BS (Doods et al., Br. J, Pharmacol.,2000, 129, 420-423). Thus the vascular effects of CGRP may beattenuated, prevented or reversed by a CORP antagonist.

CORP-mediated vasodilation of rat middle meningeal artery was shown tosensitize neurons of the trigeminal nucleus caudalis (Williamson et al.,The CORP Family: Calcitonin Gene-Related Peptide (CGRP), Amylin, andAdrenomedullin, Landes Bioscience, 2000, 245-247). Similarly, distentionof dural blood vessels during migraine headache may sensitize trigeminalneurons. Some of the associated symptoms of migraine, includingextra-cranial pain and facial allodynia, may be the result of sensitizedtrigeminal neurons (Burstein et al., Ann. Neurol. 2000, 47, 614-624). ACGRP antagonist may be beneficial in attenuating, preventing orreversing the effects of neuronal sensitization.

The ability of the compounds of the present invention to act as CGRPantagonists makes them useful pharmacological agents for disorders thatinvolve CGRP in humans and animals, but particularly in humans. Suchdisorders include migraine and cluster headache (Doods, Curr Opin InvesDrugs, 2001, 2 (9), 1261-1268; Edvinsson et al., Cephalalgia, 1994, 14,320-327); chronic tension type headache (Ashina et al., Neurology, 2000,14, 1335-1340); pain (Yu et al., Eur. J. Pharm., 1998, 347, 275-282);chronic pain (Hulsebosch et al., Pain, 2000, 86, 163-175); neurogenicinflammation and inflammatory pain (Holzer, Neurosci., 1988, 24,739-768; Delay-Goyet et al., Acta Physiol. Scanda. 1992, 146, 537-538;Salmon et al., Nature Neurosci., 2001, 4(4), 357-358); eye pain (May etal. Cephalalgia, 2002, 22, 195-196); tooth pain (Awawdeh et al., Int.Endocrin. J., 2002, 35, 30-36); non-insulin dependent diabetes mellitus(Molina et al., Diabetes, 1990, 39, 260-265); vascular disorders;inflammation (Zhang et al., Pain, 2001, 89, 265); arthritis, bronchialhyperreactivity, asthma (Foster et al., Ann. NY Acad. Sci., 1992, 657,397-404; Schini et al., Am. J. Physiol., 1994, 267, 112483-H2490; Zhenget al., J. Virol., 1993, 67, 5786-5791); shock, sepsis (Beer et al.,Crit. Care Med., 2002, 30 (8), 1794-1798); opiate withdrawal syndrome(Salmon et al., Nature Neurosci., 2001, 4(4), 357-358); morphinetolerance (Menard et al., J. Neurosci., 1996, 16 (7), 2342-2351); hotflashes in men and women (Chen et al., Lancet, 1993, 342, 49; Spetz etal., J. Urology, 2001, 166, 1720-1723); allergic dermatitis (Wallengren,Contact Dermatitis, 2000, 43 (3), 137-143); psoriasis; encephalitis,brain trauma, ischaemia, stroke, epilepsy, and neurodegenerativediseases (Rohrenbeck et al., Neurobiol. of Disease 1999, 6, 15-34); skindiseases (Geppetti and Holzer, Eds., Neurogenic Inflammation, 1996, CRCPress, Boca Raton, Fla.); neurogenic cutaneous redness, skinrosaceousness and erythema; tinnitus (Herzog et al., J. MembraneBiology, 2002, 189(3), 225); inflammatory bowel disease, irritable bowelsyndrome, (Hoffman et al. Scandinavian Journal of Gastroenterology,2002, 37(4) 414-422) and cystitis. Of particular importance is the acuteor prophylactic treatment of headache, including migraine and clusterheadache.

The present invention relates to compounds that are useful as ligandsfor CORP receptors, in particular antagonists for CGRP receptors,processes for their preparation, their use in therapy, pharmaceuticalcompositions comprising them and methods of therapy using them.

SUMMARY OF THE INVENTION

The present invention is directed to bicyclic dihydroimidazolone CGRPreceptor antagonist compounds of formula I:

(wherein variables B, G¹, G², G³, G⁴, E^(a), E^(b), E^(c), A¹, A², A³,A⁴, R⁶ and R^(PG) and Y are as described herein) which are antagonistsof CGRP receptors and which are useful in the treatment or prevention ofdiseases in which CORP is involved, such as migraine The invention isalso directed to pharmaceutical compositions comprising these compoundsand the use of these compounds and compositions in the prevention ortreatment of such diseases in which CGRP is involved.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to bicyclic dihydroimidazolonecompounds of the formula I:

wherein:

-   B is a heterocycle selected from the group consisting of:

-   wherein T, U, V, and W are each independently a carbon atom or a    nitrogen atom, and no more than two of T, U, V and W are nitrogen    atoms;-   X is selected from:    -   (1) —O—,    -   (2) —S(O)_(q)—,    -   (3) —Si(OR^(a))—C₁₋₄alkyl-, where alkyl is unsubstituted or        substituted with 1-5 halo,    -   (4) —Si(C₁₋₄alkyl)₂, where each alkyl is independently        unsubstituted or substituted with 1-5 halo-,    -   (5) —N(R⁸)—,    -   (6) —(C═O)—,    -   (7) —C(R⁸)(R^(a))—,    -   (8) —C(N(R^(b))—SO₂R^(d))(R^(a))—,    -   (9) —C(N(R^(b))(C═O)R^(a))(R^(a))—,    -   (10) —C(N(R^(b))(C═O)OR^(a))(R^(a))—,    -   (11) —CR¹⁰R¹¹—,    -   (12) —N(R¹¹)—, and    -   (13) —CR³R⁴—;-   B is unsubstituted or substituted with 1-7 substituents each    independently selected from R¹, R², R³, R⁴, R¹⁰, and R¹¹, wherein    R¹, R², and R³ are independently selected from:    -   (1) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-7        substituents each independently selected from:        -   (a) halo,        -   (b) hydroxy,        -   (c) —O—C₁₋₆ alkyl,        -   (d) —C₃₋₆ cycloalkyl,        -   (e) phenyl or heterocycle, wherein heterocycle is selected            from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,            piperidinyl, piperazinyl, pyrrolidinyl, oxazolyl, thiazolyl,            thienyl and morpholinyl, which phenyl or heterocycle is            unsubstituted or substituted with 1-5 substituents each            independently selected from: —C₁₋₆alkyl, —O—C₁₋₆alkyl, halo,            hydroxy, trifluoromethyl and —OCF₃,        -   (f) —CO₂R¹⁹        -   (g) —NR²⁰R²¹,        -   (h) —SO₂R²²,        -   (i) —CONR^(20a)R^(21a),        -   (j) trifluoromethyl,        -   (k) —OCO₂R¹⁹,        -   (l) —(NR^(20a))CO₂R¹⁹,        -   (m) —O(CO)NR^(20a)R^(21a),        -   (n) —(NR¹⁹)(CO)NR^(20a)R^(21a), and        -   (o) —O—C₃₋₆cycloalkyl,    -   (2) —C₃₋₆cycloalkyl, which is unsubstituted or substituted with        1-7 substituents each independently selected from:        -   (a) halo,        -   (b) hydroxy,        -   (c) —O—C₁₋₆alkyl,        -   (d) trifluoromethyl,        -   (e) phenyl, which is unsubstituted or substituted with 1-5            substituents each independently selected from: —C₁₋₆alkyl,            —O—C₁₋₆alkyl, halo, hydroxy and trifluoromethyl,    -   (3) phenyl or heterocycle, wherein heterocycle is selected from:        pyridyl, pyrimidinyl, pyrazinyl, thienyl, pyridazinyl,        pyrrolidinyl, azetidinyl, thiazolyl, isothiazolyl, oxazolyl,        isoxazolyl, imidazolyl, triazolyl, tetrazolyl, azepanyl,        benzimidazolyl, benzopyranyl, benzofuryl, benzothiazolyl,        benzoxazolyl, chromanyl, furyl, imidazolinyl, indolinyl,        indolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl,        isoindolinyl, tetrahydroisoquinolinyl, 2-oxopiperazinyl,        2-oxopiperidinyl, 2-oxopyrrolidinyl, pyrazolidinyl, pyrazolyl,        pyrrolyl, quinazolinyl, tetrahydrofuryl, thiazolinyl, purinyl,        naphthyridinyl, quinoxalinyl, 1,3-dioxolanyl, oxadiazolyl,        piperidinyl, tetrahydropyranyl, tetrahydrothienyl,        tetrahydrothiopyranyl, and morpholinyl, which phenyl or        heterocycle is unsubstituted or substituted with 1-5        substituents each independently selected from:        -   (a) —C₁₋₆alkyl, which is unsubstituted or substituted with            1-6 fluoro,        -   (b) halo,        -   (c) hydroxy,        -   (d) —O—C₁₋₆alkyl, which is unsubstituted or substituted with            1-6 fluoro,        -   (e) —C₃₋₆cycloalkyl,        -   (f) phenyl or heterocycle, wherein heterocycle is selected            from: pyridyl, pyrimidinyl, pyrazinyl, thienyl, or            morpholinyl, which is unsubstituted or substituted with 1-5            substituents where the substituents are independently            selected from: —C₁₋₆alkyl, —O—C₁₋₆alkyl, halo, hydroxy and            trifluoromethyl,        -   (g) —CO₂R¹⁹,        -   (h) —(CO)R¹⁹,        -   (i) —NR²⁰R²¹,        -   (j) —CONR²⁰R²¹,        -   (k) oxo, and        -   (l) —S(O)_(q)R²²,    -   (4) halo,    -   (5) oxo,    -   (6) hydroxy,    -   (7) —O—C₁₋₆alkyl which is unsubstituted or substituted with 1-5        halo,    -   (8) —CN,    -   (9) —CO₂R¹⁹,    -   (10) —NR²⁰R²¹,    -   (11) —SO₂R²²,    -   (12) —CONR^(20a)R^(21a),    -   (13) —OCO₂R¹⁹,    -   (14) —(NR^(20a))CO₂R¹⁹,    -   (15) —O(CO)NR^(20a)R^(21a),    -   (16) —(NR¹⁹)(CO)NR^(20a)R^(21a),    -   (17) —(CO)—(CO)NR^(20a)R^(21a),    -   (18) —(CO)—(CO)OR¹⁹,    -   (19) —SO₂NR^(20a)R^(21a), and    -   (20) hydrogen;    -   or R³ and R⁴ and the carbon atom to which they are attached join        to form a ring selected from cyclopropyl, cyclobutyl,        cyclopentyl, cyclohexyl, cycloheptyl, dioxolanyl, dioxanyl,        aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,        morpholinyl, tetrahydrofuranyl, tetrahydropyranyl,        tetrahydrothiapyranyl, oxetanyl, thietanyl and        tetrahydrothienyl, wherein the sulfur is optionally oxidized to        the sulfone or sulfoxide, which ring is unsubstituted or        substituted with 1-5 substituents each independently selected        from:        -   (a) —C₁₋₆alkyl, which is unsubstituted or substituted with            1-3 substituents each independently selected from:            -   (1) halo,            -   (ii) —OR^(a),            -   (iii) —C₃₋₆cycloalkyl,            -   (iv) —CO₂R^(a),            -   (v) —NR^(b)R^(c),            -   (vi) —S(O)_(q)R^(d),            -   (vii) —C(═O)NR^(b)R^(c), and            -   (viii) phenyl,        -   (b) phenyl or heterocycle, wherein heterocycle is selected            from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,            piperdinyl, piperazinyl, pyrrolidinyl, thienyl, morpholinyl,            thiazolyl and oxazolyl, wherein the phenyl or heterocycle is            optionally fused to the ring, and which phenyl or            heterocycle is unsubstituted or substituted with 1-5            substituents each independently selected from:            -   (i) halo,            -   (ii) —C₁₋₆alkyl, which is unsubstituted or substituted                with 1-5 halo,            -   (iii) —OR^(a),            -   (iv) —CO₂R^(a),            -   (v) —O(C═O)R^(a),            -   (vi) —CN,            -   (vii) —NR^(b)R^(c),            -   (viii) oxo,            -   (ix) —C(═O)NR^(b)R^(c),            -   (x) —N(R^(b))C(═O)R^(a),            -   (xi) —N(R^(b))CO₂R^(a),            -   (xii) —O(C═O)NR^(b)R^(c), and            -   (xiii) —S(O)_(q)R^(d),        -   (c) —OR^(a),        -   (d) halo,        -   (e) —CO₂R^(a),        -   (f) —C(═O)NR^(b)R^(c),        -   (g) —S(O)_(q)R^(d),        -   (h) —CN,        -   (i) —NR^(b)R^(c),        -   (j) —N(R^(b))C(═O)R^(a),        -   (k) —N(R^(b))SO₂R^(d),        -   (l) —O—CO₂R^(d),        -   (m) —O—(C═O)—NR^(b)R^(c),        -   (n) —NR^(b)—(C═O)—NR^(b)R^(c),        -   (o) —C(═O)R^(a), and        -   (p) oxo;-   A¹ and A³ are independently selected from:    -   (1) —O—,    -   (2) —S(O)_(q)—,    -   (3) —Si(OR^(a))(C₁₋₄alkyl)-, where alkyl is unsubstituted or        substituted with halo,    -   (4) —Si(C₁₋₄alkyl)₂-, where each alkyl is independently        unsubstituted or substituted with 1-5 halo-,    -   (5) —CR^(e)R^(f)—,    -   (6) —N(R⁴)—,    -   (7) —(C═O)—, and    -   (8) a bond;-   A² and A⁴ are independently selected from:    -   (1) —O—,    -   (2) —S(O)_(q)—,    -   (3) —Si(OR^(a))(C₁₋₄alkyl)-, where alkyl is unsubstituted or        substituted with halo,    -   (4) —Si(C₁₋₄alkyl)2-, where each alkyl is independently        unsubstituted or substituted with 1-5 halo-,    -   (5) —CR^(e)R^(f)—,    -   (6) —N(R⁴)—, and    -   (7) —(C═O)—;-   E^(a), E^(b), and E^(c) are each independently selected from:    -   (1) —C(R⁵)═,    -   (2) —N═, and    -   (3) —((N⁺—O—)═;-   G¹ is selected from:    -   (1) a bond,    -   (2) —CR^(e)R^(f)—,    -   (3) —CR^(e)R^(f)—CH₂—,    -   (4) —CH₂—CR^(e)R^(f)—, and    -   (5) —(C═O)—;-   G² is selected from:    -   (1) a bond,    -   (2) —CR^(e)R^(f)—,    -   (3) —CR^(e)R^(f)—CH₂—,    -   (4) —CH₂—CR^(e)R^(f)—,    -   (5) —(C═O)—,    -   (6) —N(R⁴)—,    -   (7) —O—,    -   (8) —S(O)_(q)—,    -   (9) —SiR^(g)R^(h)—,    -   (10) —C(R^(i))═C(R^(j))—, and    -   (11) —C≡C—;-   G³ is selected from:    -   (1) a bond,    -   (2) —CR^(e)R^(f)—,    -   (3) —N(R⁴)—,    -   (4) —O—,    -   (5) —S(O)_(q)—,    -   (6) —SiR^(g)R^(h)—,    -   (7) —C(R^(i))═C(R^(j))—,    -   (8) —C≡C—, and    -   (9) —(C═O)—;-   G⁴ is selected from:    -   (1) —CR^(e)R^(f)—,    -   (2) —N(R⁴)—,    -   (3) —O—,    -   (4) —S(O)_(q)—,    -   (5) —SiR^(g)R^(h)—,    -   (6) —C(R^(i))═C(R^(j))—, and    -   (7) —C≡C—;-   R⁴ is independently selected from:    -   (1) hydrogen,    -   (2) —C(═O)R^(a),    -   (3) —CO₂R^(a),    -   (4) —S(═O)R^(d),    -   (5) —SO₂R^(d),    -   (6) —C(═O)NR^(b)R^(c),    -   (7) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-5        substituents each independently selected from:        -   (a) halo,        -   (b) —OR^(a),        -   (c) —C₃₋₆cycloalkyl,        -   (d) phenyl or heterocycle, wherein said heterocycle is            selected from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,            piperidinyl, piperazinyl, pyrrolidinyl, thienyl,            morpholinyl, thiazolyl and oxazolyl, which phenyl or            heterocycle is unsubstituted or substituted with 1-5            substituents each independently selected from:            -   (i) halo,            -   (ii) —C₁₋₆alkyl, which is unsubstituted or substituted                with 1-5 halo,            -   (iii) —OR^(a),            -   (iv) —NR^(b)R^(c),            -   (v)—C(═O)R^(a),            -   (vi) —CO₂R^(a), and            -   (vii) oxo;        -   (e) —CO₂R^(a),        -   (f) —C(═O)NR^(b)R^(c),        -   (g) —S(O)_(q)R^(d),        -   (h) —CN,        -   (i) —NR^(b)R^(c),        -   (j) —N(R^(b))C(═O)R^(a),        -   (k) —N(R^(b))SO₂R^(d),        -   (l) —CF₃,        -   (m) —O—CO₂R^(d),        -   (n) —O—(C═O)—NR^(b)R^(c),        -   (o) —NR^(b)—(C═O)—NR^(b)R^(c), and        -   (p) —C(═O)R^(a);    -   (8) —C₃₋₆cycloalkyl, which is unsubstituted or substituted with        1-6 substituents each independently selected from:        -   (a) halo,        -   (b) —CN,        -   (c) —OR^(a), and        -   (d) C₁₋₆alkyl, which is unsubstituted or substituted with            1-6 halo;-   R⁵ is independently selected from:    -   (1) hydrogen,    -   (2) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-7        substituents each independently selected from:        -   (a) halo,        -   (b) hydroxy,        -   (c) —OC₁₋₆alkyl,        -   (d) —C₃₋₆cycloalkyl,        -   (e) phenyl,        -   (f) —CONR^(20a)R^(21a),        -   (g) —CO₂R¹⁹, and        -   (h) —NR²⁰R²¹,    -   (3) —C₃₋₆cycloalkyl, which is unsubstituted or substituted with        1-6 fluoro,    -   (4) phenyl or heterocycle, wherein heterocycle is selected from:        pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperdinyl,        piperazinyl, pyrrolidinyl, thienyl, morpholinyl, thiazolyl and        oxazolyl, which phenyl or heterocycle is unsubstituted or        substituted with 1-5 substituents each independently selected        from:        -   (a) —C₁₋₄alkyl, which is unsubstituted or substituted with            1-5 fluoro,        -   (b) halo,        -   (c) —CN,        -   (d) hydroxy, and        -   (e) —O—C₁₋₆alkyl, which is unsubstituted or substituted with            1-6 fluoro,    -   (5) halo,    -   (6) hydroxy,    -   (7) —OC₁₋₆alkyl, which is unsubstituted or substituted with 1-5        halo,    -   (8) —CN,    -   (9) —CO₂R¹⁹,    -   (10) —NR²⁰R²¹,    -   (11) —SO₂R²²,    -   (12) —CONR^(20a)R^(21a),    -   (13) —OCO₂R¹⁹, and    -   (14) —(NR^(20a))CO₂R¹⁹;-   R⁶ is selected from:    -   (1) hydrogen;    -   (2) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-6        substituents each independently selected from:        -   (a) halo,        -   (b) —O—C₁₋₆alkyl, which is unsubstituted or substituted with            1-6 fluoro,        -   (c) —C₃₋₆cycloalkyl, which is unsubstituted or substituted            with 1-6 fluoro, and        -   (d) phenyl or heterocycle, wherein heterocycle is selected            from: azepinyl, azepanyl, azetidinyl, benzimidazolyl,            benzisoxazolyl, benzofuranyl, benzofurazanyl, benzopyranyl,            benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl,            benzoxazolyl, benzopyrazolyl, benzotriazolyl,            dibenzofuranyl, dihydrobenzofuryl, dihydrobenzothienyl,            dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone,            furyl, furanyl, imidazolidinyl, imidazolinyl, imidazolyl,            indolinyl, indolyl, isoindolinyl, isoquinolinyl,            isothiazolidinyl, isothiazolyl, morpholinyl, naphthyridinyl,            oxazolyl, oxadiazolyl, 2-oxoazepinyl, 4-oxonaphthyridinyl,            2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl,            2-oxopyridyl, 2-oxoquinolinyl, piperidyl, piperazinyl,            pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyridinyl,            pyridyl, pyrimidinyl, pyrimidyl, pyrrolidinyl, pyrrolyl,            quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuranyl,            tetrahydrofuryl, tetrahydroimidazopyridinyl,            tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl,            thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl            sulfone, thiazolyl, thiazolinyl, thienofuryl, thienothienyl,            thienyl, isoxazolyl, tetrahydrothienyl, tetrahydropyranyl,            oxetanyl, tetrahydrothiapyranyl, thietanyl, and triazolyl,            which phenyl or heterocycle is unsubstituted or substituted            with 1-3 substituents each independently selected from:            —C₁₋₆alkyl, —O—C₁₋₆alkyl, halo, hydroxy, trifluoromethyl,            —CN, and —OCF₃,    -   (3) phenyl or heterocycle, wherein heterocycle is selected from:        azepinyl, azepanyl, azetidinyl, benzimidazolyl, benzisoxazolyl,        benzofuranyl, benzofurazanyl, benzopyranyl, benzothiopyranyl,        benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl,        benzopyrazolyl, benzotriazolyl, dibenzofuranyl,        dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl,        dihydrobenzothiopyranyl sulfone, furyl, furanyl, imidazolidinyl,        imidazolinyl, imidazolyl, indolinyl, indolyl, isoindolinyl,        isoquinolinyl, isothiazolidinyl, isothiazolyl, morpholinyl,        naphthyridinyl, oxazolyl, oxadiazolyl, 2-oxoazepinyl,        4-oxonaphthyridinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,        2-oxopyrrolidinyl, 2-oxopyridyl, 2-oxoquinolinyl, piperidyl,        piperazinyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl,        pyridinyl, pyridyl, pyrimidinyl, pyrimidyl, pyrrolidinyl,        pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl,        tetrahydrofuranyl, tetrahydrofuryl, tetrahydroimidazopyridinyl,        tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl,        thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl        sulfone, thiazolyl, thiazolinyl, thienofuryl, thienothienyl,        thienyl, isoxazolyl, tetrahydrothienyl, tetrahydropyranyl,        oxetanyl, tetrahydrothiapyranyl, thietanyl, and triazolyl, which        phenyl or heterocycle is unsubstituted or substituted with 1-3        substituents each independently selected from:        -   (a) halo,        -   (b) —OR^(a),        -   (c) —C₃₋₆cycloalkyl, which is unsubstituted or substituted            with 1-6 fluoro,        -   (d) phenyl, which is unsubstituted or substituted with 1-5            substituents each independently selected from:            -   (i) halo,            -   (ii) —CN,            -   (iii) —C₁₋₆alkyl, which is unsubstituted or substituted                with 1-6 halo, and            -   (iv) —OR^(a),        -   (e) —CO₂R^(a),        -   (f) —C(═O)NR^(b)R^(c),        -   (g) —S(O)_(q)R^(d),        -   (h) —CN,        -   (i) —NR^(b)R^(c),        -   (j) —N(R^(b))C(═O)R^(a),        -   (k) —N(R^(b))SO₂R^(d),        -   (l) —O—CO₂R^(d),        -   (m) —O—(C═O)—NR^(b)R^(c),        -   (n) —NR^(b)—(C═O)—NR^(b)R^(c),        -   (o) —C(═O)R^(a), and        -   (p) —C₁₋₆alkyl, which is unsubstituted or substituted with            1-6 halo,    -   (4) —O—C₁₋₆alkyl, which is unsubstituted or substituted with 1-5        halo,    -   (5) —CN,    -   (6) —CO₂R19,    -   (7) —NR²⁰R²¹, and    -   (8) —CONR^(20a)R^(21a)    -   (9) —C₁₋₆cycloalkyl, which is unsubstituted or substituted with        1-5 substituents each independently selected from:        -   (a) halo,        -   (b) —CN,        -   (c) —C₁₋₆alkyl, which is unsubstituted or substituted with            1-5 halo,        -   (d) —OR^(a), and        -   (e) phenyl, which is unsubstituted or substituted with 1-5            substituents where the substituents are each independently            selected from:            -   (i) —OR^(a),            -   (ii) halo,            -   (iii) —CN, and            -   (iv) —C₁₋₆alkyl, which is unsubstituted or substituted                with 1-5 halo;-   R⁸ is independently selected from:    -   (1) hydrogen,    -   (2) —C(═O)R^(a),    -   (3) —CO₂R^(a),    -   (4) —S(═O)R^(d),    -   (5) —SO₂R^(d),    -   (6) —C(═O)NR^(b)R^(c),    -   (7) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-5        substituents each independently selected from:        -   (a) halo,        -   (b) —OR^(a),        -   (c) —C₃₋₆cycloalkyl,        -   (d) phenyl or heterocycle, wherein said heterocycle is            selected from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,            piperidinyl, piperazinyl, pyrrolidinyl, thienyl,            morpholinyl, thiazolyl and oxazolyl, which phenyl or            heterocycle is unsubstituted or substituted with 1-5            substituents each independently selected from:            -   (i) halo,            -   (ii) —C₁₋₆alkyl, which is unsubstituted or substituted                with 1-5 halo,            -   (iii) —OR^(a),            -   (iv) —NR^(b)R^(c),            -   (v) —C(═O)R^(a),            -   (vi) —CO₂R^(a),            -   (vii) oxo, and            -   (viii) —CN,        -   (e) —CO₂R^(a),        -   (f) —C(═O)NR^(b)R^(c),        -   (g) —S(O)_(q)R^(d),        -   (h) —CN,        -   (i) —NR^(b)R^(c),        -   (j) —N(R^(b))C(═O)R^(a),        -   (k) —N(R^(b))SO₂R^(d),        -   (l) —CF₃,        -   (m) —O—CO₂R^(d),        -   (n) —O—(C═O)—NR^(b)R^(c),        -   (o) —NR^(b)—(C═O)—NR^(b)R^(c), and        -   (p) —C(═O)R^(a),    -   (8) —C₃₋₆cycloalkyl, which is unsubstituted or substituted with        1-6 substituents each independently selected from:        -   (a) halo,        -   (b) —CN,        -   (c) —OR^(a), and        -   (d) C₁₋₆alkyl, which is unsubstituted or substituted with            1-6 halo;    -   or R⁴ and R⁸ and the atoms to which they are attached join to        form a 4-, 5-, 6- or 7-membered alkyl- or heteroalkyl-ring        optionally containing an additional heteroatom selected from N,        O, and S, wherein the sulfur is optionally oxidized to the        sulfone or sulfoxide, which ring is unsubstituted or substituted        with 1-4 substituents each independently selected from:        -   (a) halo,        -   (b) phenyl, which is unsubstituted or substituted with 1-3            substituents each independently selected from: halo, OR^(a),            CN, and —C(═O)OR^(a),        -   (c) —OR^(a), and        -   (d) —C₁₋₆alkyl, which is unsubstituted or substituted with            1-6 halo;-   R¹⁰ is independently selected from:    -   (1) hydrogen,    -   (2) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-5        substituents each independently selected from:        -   (a) halo,        -   (b) —OR^(a),        -   (c) —CN,        -   (d) phenyl, and        -   (e) —C₃₋₆cycloalkyl, which is unsubstituted or substituted            with 1-6 halo,    -   (3) —C₃₋₆cycloalkyl, which is unsubstituted or substituted with        1-6 halo;-   R¹¹ is independently selected from the group consisting of:

phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl,anthryl, azepinyl, azepanyl, azetidinyl, benzimidazolyl, benzisoxazolyl,benzofuranyl, benzofurazanyl, benzopyranyl, benzothiopyranyl,benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, benzopyrazolyl,benzotriazolyl, chromanyl, cinnolinyl, dibenzofuranyl,dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl,dihydrobenzothiopyranyl sulfone, furyl, furanyl, imidazolidinyl,imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl,isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl,morpholinyl, naphthyridinyl, oxazolyl, oxadiazolyl, 2-oxoazepinyl,4-oxonaphthyridinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolidinyl, 2-oxopyridyl, 2-oxoquinolinyl, piperidyl,piperazinyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl,pyridinyl, pyridyl, pyrimidinyl, pyrimidyl, pyrrolidinyl, pyrrolyl,quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuranyl,tetrahydrofuryl, tetrahydroimidazopyridinyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, tetrazolyl, thiamorpholinyl, thiamorpholinylsulfoxide, thiamorpholinyl sulfone, thiazolyl, thiazolinyl, thienofuryl,thienothienyl, thienyl, triazolyl, isoxazolyl, tetrahydrothienyl,tetrahydropyranyl, oxetanyl, tetrahydrothiapyranyl, and thietanyl, whereR¹¹ is unsubstituted or substituted with 1-5 substituents eachindependently selected from R¹², R¹³, R¹⁴, R^(15a) and R^(15b);

-   R¹², R¹³, R¹⁴, R^(15a) and R^(15b) are each independently selected    from:    -   (1) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-5        substituents each independently selected from:        -   (a) halo,        -   (b) —OR^(a),        -   (c) —C₃₋₆cycloalkyl,        -   (d) phenyl or heterocycle, wherein said heterocycle is            selected from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,            piperdinyl, piperazinyl, pyrrolidinyl, thienyl, morpholinyl,            thiazolyl and oxazolyl, which phenyl or heterocycle is            unsubstituted or substituted with 1-5 substituents each            independently selected from:            -   (i) halo,            -   (ii) —C₁₋₆alkyl, which is unsubstituted or substituted                with 1-5 halo, and            -   (iii) —OR^(a),        -   (e) —CO₂R^(a),        -   (f) —C(═O)NR^(b)R^(c),        -   (g) —S(O)_(q)R^(d),        -   (h) —CN,        -   (i) —NR^(b)R^(c),        -   (j) —N(R^(b))C(═O)R^(a),        -   (k) —N(R^(b))SO₂R^(d),        -   (l) —CF₃,        -   (m) —O—CO₂R^(d),        -   (n) —O—(C═O)—NR^(b)R^(c),        -   (o) —NR^(b))—(C═O)—NR^(b)R^(c), and        -   (p) —C(═O)R^(a),    -   (2) —C₁₋₆cycloalkyl, which is unsubstituted or substituted with        1-5 substituents each independently selected from:        -   (a) halo,        -   (b) —CN,        -   (c) —C₁₋₆alkyl, which is unsubstituted or substituted with            1-5 halo,        -   (d) —OR^(a), and        -   (e) phenyl, which is unsubstituted or substituted with 1-5            substituents where the substituents are each independently            selected from:            -   (i) —OR^(a),            -   (ii) halo,            -   (iii) —CN, and            -   (iv) —C₁₋₆alkyl, which is unsubstituted or substituted                with 1-5 halo,    -   (3) phenyl or heterocycle, wherein said heterocycle is selected        from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperdinyl,        piperazinyl, pyrrolidinyl, thienyl, morpholinyl, thiazolyl and        oxazolyl, which phenyl or heterocycle is unsubstituted or        substituted with 1-5 substituents each independently selected        from:        -   (a) halo,        -   (b) —OR^(a),        -   (c) —C₃₋₆cycloalkyl, which is unsubstituted or substituted            with 1-6 halo,        -   (d) phenyl, which is unsubstituted or substituted with 1-5            substituents each independently selected from:            -   (i) halo,            -   (ii) —C₁₋₆alkyl, which is unsubstituted or substituted                with 1-6 halo, and            -   (iii) —OR^(a),        -   (e) —CO₂R^(a),        -   (f) —C(═O)NR^(b)R^(c),        -   (g) —S(O)_(q)R^(d),        -   (h) —CN,        -   (i) —NR^(b)R^(c),        -   (j) —N(R^(b))C(═O)R^(a),        -   (k) —N(R^(b))SO₂R^(d),        -   (l) —O—CO₂R^(d),        -   (m) —O—(C═O)—NR^(b)R^(c),        -   (n) —NR^(b)—(C═O)—NR^(b)R^(c),        -   (o) —C(═O)R^(a), and        -   (p) —C₁₋₆alkyl, which is unsubstituted or substituted with            1-6 halo,    -   (4) halo,    -   (5) oxo,    -   (6) —OR^(a),    -   (7) —CN,    -   (8) —CO₂R^(a),    -   (9) —C(═O)R^(a),    -   (10) —NR^(b)R^(c),    -   (11) —S(O)_(q)R^(d),    -   (12) —C(═O)NR^(b)R^(c),    -   (13) —O—CO₂R^(d),    -   (14) —N(R^(b))CO₂R^(d),    -   (15) —O—(C═O)—NR^(b)R^(c),    -   (16) —NR^(b)—(C═O)—NR^(b)R^(c),    -   (17) —SO₂NR^(b)R^(c),    -   (18) —N(R^(b))SO₂R^(d),    -   or R^(15a) and R^(15b) and the atom(s) to which they are        attached join to form a ring selected from cyclopropyl,        cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, aziridinyl,        azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,        thietanyl and tetrahydrothienyl, wherein the sulfur is        optionally oxidized to the sulfone or sulfoxide, which ring is        unsubstituted or substituted with 1-5 substituents each        independently selected from:        -   (a) —C₁₋₆alkyl, which is unsubstituted or substituted with            1-3 substituents each independently selected from:            -   (i) halo,            -   (ii) —OR^(a),            -   (iii) —C₃₋₆cycloalkyl, which is unsubstituted or                substituted with 1-6 halo,            -   (iv) —CO₂R^(a),            -   (v) —NR^(b)R^(c),            -   (vi) —S(O)_(q)R^(d),            -   (vii) —C(═O)NR^(b)R^(c), and            -   (viii) phenyl,        -   (b) phenyl or heterocycle, wherein said heterocycle is            selected from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,            piperidinyl, piperazinyl, pyrrolidinyl, thienyl,            morpholinyl, thiazolyl and oxazolyl, which phenyl or            heterocycle is unsubstituted or substituted with 1-5            substituents each independently selected from:            -   (i) halo,            -   (ii) —C₁₋₆alkyl, which is unsubstituted or substituted                with 1-5 halo, and            -   (iii) —OR^(a),        -   (c) —OR^(a),        -   (d) halo,        -   (e) —CO₂R^(a),        -   (f) —C(═O)NR^(b)R^(c),        -   (g) —S(O)_(q)R^(d),        -   (h) —CN,        -   (i) —NR^(b)R^(c),        -   (j) —N(R^(b))C(═O)R^(a),        -   (k) —N(R^(b))SO₂R^(d),        -   (l) —O—CO₂R^(d),        -   (m) —O—(C═O)—NR^(b)R^(c),        -   (n) —NR^(b)—(C═O)—NR^(b)R^(c), and        -   (o) —C(═O)R^(a);-   R¹⁹ is independently selected from:    -   (1) hydrogen,    -   (2) —C ₁₋₆alkyl, which is unsubstituted or substituted with 1-6        substituents, each independently selected from:        -   (a) halo,        -   (b) hydroxy,        -   (c) —OC₁₋₆alkyl, which is unsubstituted or substituted with            1-5 halo,        -   (d) —C₃₋₆cycloalkyl, which is unsubstituted or substituted            with 1-6 halo, and        -   (e) phenyl, which is unsubstituted or substituted with 1-5            substituents each independently selected from:            -   (i) —C₁₋₄alkyl,            -   (ii) —OC₁₋₆alkyl,            -   (iii) halo,            -   (iv) trifluoromethyl, and            -   (v) —OCF₃,    -   (3) -C₃₋₆ cycloalkyl, which is unsubstituted or substituted with        1-6 substituents, substituents each independently selected from:        -   (a) halo,        -   (b) hydroxy,        -   (c) —O—C₁₋₆alkyl, which is unsubstituted or substituted with            1-5 halo,        -   (d) —C₁₋₆alkyl, which is unsubstituted or substituted with            1-5 halo, and        -   (e) phenyl,    -   (4) phenyl or heterocycle, wherein heterocycle is selected from:        pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl,        pyrrolidinyl, thiazolyl, oxazolyl, imidazolyl, triazolyl,        tetrazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl,        imidazolinyl, indolinyl, indolyl, quinolinyl, isoquinolinyl,        tetrahydroquinolinyl, isoindolinyl, tetrahydroisoquinolinyl,        tetrahydrofuryl, quinoxalinyl, piperidinyl, piperazinyl, and        morpholinyl, which phenyl or heterocycle is unsubstituted or        substituted with 1-5 substituents each independently selected        from:        -   (a) halo,        -   (b) —C₁₋₆alkyl, which is unsubstituted or substituted with            1-5 halo        -   (c) —OC₁₋₆alkyl, which is unsubstituted or substituted with            1-5 halo        -   (d) —C₃₋₆cycloalkyl,        -   (e) oxo,        -   (f) —CN,        -   (g) hydroxy, and        -   (h) phenyl;-   R²⁰ and R²¹ are each independently selected from:    -   (1) hydrogen,    -   (2) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-6        substituents each independently selected from:        -   (a) halo,        -   (b) hydroxy,        -   (c) —OCF₃,        -   (d) —C₃₋₆cycloalkyl, which is unsubstituted or substituted            with 1-6 halo, and        -   (e) phenyl, which is unsubstituted or substituted with 1-5            substituents each independently selected from:            -   (i) —C₁₋₆alkyl, which is unsubstituted or substituted                with 1-5 halo,            -   (ii) —OC₁₋₆alkyl, which is unsubstituted or substituted                with 1-5 halo,            -   (iii) —CN            -   (iv) halo, and            -   (v) trifluoromethyl,    -   (3) —C₃₋₆cycloalkyl, which is unsubstituted or substituted with        1-6 halo,    -   (4) phenyl, which is unsubstituted or substituted with 1-5        substituents each independently selected from:        -   (a) —C₁₋₆alkyl, which is unsubstituted or substituted with            1-5 halo,        -   (b) —OC₁₋₆alkyl, which is unsubstituted or substituted with            1-5 halo,        -   (c) halo,        -   (d) hydroxy,        -   (e) trifluoromethyl,        -   (f) —OCF₃, and        -   (g) —CN,    -   (5) —COR¹⁹, and    -   (6) —SO₂R₂₂;-   R^(20a) and R^(21a) are each independently selected from:    -   (1) hydrogen,    -   (2) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-6        substituents each independently selected from:        -   -   (a) —O—C₁₋₆alkyl, which is unsubstituted or substituted                with 1-5 halo,

        -   (b) halo,

        -   (c) hydroxy,

        -   (d) —OCF₃,

        -   (e) —C₃₋₆cycloalkyl, and

        -   (f) phenyl, which is unsubstituted or substituted with 1-5            substituents each independently selected from:            -   (i) —C₁₋₆alkyl, which is unsubstituted or substituted                with 1-5 halo,            -   (ii) —OC₁₋₆alkyl, which is unsubstituted or substituted                with 1-5 halo,            -   (iii) —CN            -   (iv) halo, and            -   (v) trifluoromethyl,    -   (3) —C₃₋₆cycloalkyl, which is unsubstituted or substituted with        1-5 halo,    -   (4) phenyl, which is unsubstituted or substituted with 1-5        substituents each independently selected from:        -   (a) —C₁₋₆alkyl, which is unsubstituted or substituted with            1-5 halo,        -   (b) —OC₁₋₆alkyl, which is unsubstituted or substituted with            1-5 halo,        -   (c) halo,        -   (d) hydroxy,        -   (e) trifluoromethyl,        -   (f) —OCF₃, and        -   (g) —CN,-   or where R^(20a) and R^(21a) join to form a ring selected from    azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, piperazinyl and    morpholinyl, which ring is unsubstituted or substituted with 1-5    substituents each independently selected from:    -   (1) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-5        halo,    -   (2) —O—C₁₋₆alkyl, which is unsubstituted or substituted with 1-5        halo,    -   (3) halo    -   (4) hydroxy    -   (5) phenyl, which is unsubstituted or substituted with 1-5        substituents each independently selected from:        -   (a) —C₁₋₄alkyl, which is unsubstituted or substituted with            1-3 halo,        -   (b) —O—C₁₋₄alkyl, which is unsubstituted or substituted with            1-3 halo, and        -   (c) halo,    -   (6) benzyl, which is unsubstituted or substituted with 1-5        substituents each independently selected from:        -   (a) —C₁₋₄alkyl, which is unsubstituted or substituted with            1-3 halo,        -   (b) —OC₁₋₄alkyl, which is unsubstituted or substituted with            1-3 halo, and        -   (c) halo,    -   (7) —COR¹⁹, and    -   (8) —SO₂R²²;-   R²² is selected from:    -   (1) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-6        fluoro,    -   (2) —C₃₋₆cycloalkyl, which is unsubstituted or substituted with        1-5 halo,    -   (3) phenyl or heterocycle, wherein heterocycle is selected from:        pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl,        piperazinyl, pyrrolidinyl, thienyl and morpholinyl, which phenyl        or heterocycle is unsubstituted or substituted with 1-5        substituents each independently selected from:        -   (a) —C₁₋₆alkyl, which is unsubstituted or substituted with            1-5 halo,        -   (b) —O—C₁₋₆alkyl, which is unsubstituted or substituted with            1-5 halo,        -   (c) halo,        -   (d) hydroxy,        -   (e) trifluoromethyl,        -   (f) —OCF₃,        -   (g) —CN, and        -   (h) benzyl, which is unsubstituted or substituted with 1-5            substituents each independently selected from:            -   (i) —C₁₋₆alkyl, which is unsubstituted or substituted                with 1-5 halo,            -   (ii) —O—C₁₋₆alkyl, which is unsubstituted or substituted                with 1-5 halo,            -   (iii) halo, and            -   (iv) trifluoromethyl;-   R^(PG) is selected from:    -   (1) hydrogen,    -   (2) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-6        substituents each independently selected from:        -   (a) —O—C₁₋₆alkyl, which is unsubstituted or substituted with            1-5 halo,        -   (b) halo,        -   (c) hydroxy,        -   (d) —OCF₃,        -   (e) —C₃₋₆cycloalkyl, and        -   (f) phenyl, which is unsubstituted or substituted with 1-5            substituents each independently selected from:            -   (i) —C₁₋₆alkyl, which is unsubstituted or substituted                with 1-6 halo,            -   (ii) —OR^(a),            -   (iii) —CN            -   (iii) halo, and            -   (iv) trifluoromethyl,    -   (3) —CH₂OR^(a),    -   (4) —CH₂—O—CH₂CH₂Si(CH₃)₃,-   R^(a) is independently selected from:    -   (1) hydrogen,    -   (2) C₁₋₆alkyl, which is unsubstituted or substituted with 1-7        substituents each independently selected from:        -   (a) halo,        -   (b) —O—C₁₋₆alkyl, which is unsubstituted or substituted with            1-6 halo,        -   (c) hydroxyl,        -   (d) —C₃₋₆cycloalkyl, which is unsubstituted or substituted            with 1-6 halo,        -   (e) —CN, and        -   (f) phenyl or heterocycle wherein said heterocycle is            selected from pyridyl, pyrimidinyl, thienyl, pyridazinyl,            piperidinyl, azetidinyl, furanyl, piperazinyl, pyrrolidinyl,            morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and            pyrazinyl, which phenyl or heterocycle is unsubstituted or            substituted with 1-3 substituents each independently            selected from:            -   (i) halo,            -   (ii) —O—C₁₋₆alkyl, which is unsubstituted or substituted                with 1-6 halo,            -   (iii) —CN,            -   (iv) nitro,            -   (v) hydroxyl, and            -   (vi) —C₁₋₆alkyl, which is unsubstituted or substituted                with 1-6 halo,    -   (3) phenyl or heterocycle wherein said heterocycle is selected        from pyridyl, pyrimidinyl, thienyl, pyridazinyl, piperidinyl,        azetidinyl, furanyl, piperazinyl, pyrrolidinyl, morpholinyl,        tetrahydrofuranyl, tetrahydropyranyl and pyrazinyl, which phenyl        or heterocycle is unsubstituted or substituted with 1-3        substituents each independently selected from:        -   (a) halo,        -   (b) —CN,        -   (c) —O—C₁₋₆alkyl, which is unsubstituted or substituted with            1-6 halo,        -   (d) nitro,        -   (e) hydroxyl, and        -   (f) —C₁₋₆alkyl, which is unsubstituted or substituted with            1-6 halo, and    -   (4) —C₃₋₆cycloalkyl, which is unsubstituted or substituted with        1-6 halo;-   R^(b) and R^(c) are independently selected from:    -   (1) hydrogen,    -   (2) C₁₋₆alkyl, which is unsubstituted or substituted with 1-7        substituents each independently selected from:        -   (a) halo,        -   (b) —OR^(a),        -   (c) —CN,        -   (d) —CO₂R^(a),        -   (e) phenyl or heterocycle, wherein said heterocycle is            selected from pyridyl, pyrimidinyl, thienyl, pyridazinyl,            piperidinyl, azetidinyl, furanyl, piperazinyl, pyrrolidinyl,            morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and            pyrazinyl, which phenyl or heterocycle is unsubstituted or            substituted with 1-3 substituents each independently            selected from:            -   (i) halo,            -   (ii) —OR^(a),            -   (iii) —C₁₋₆alkyl, which is unsubstituted or substituted                with 1-6 halo, and            -   (iv) nitro,    -   (3) phenyl or heterocycle, wherein said heterocycle is selected        from pyridyl, pyrimidinyl, thienyl, pyridazinyl, piperidinyl,        azetidinyl, furanyl, piperazinyl, pyrrolidinyl, morpholinyl,        tetrahydrofuranyl, tetrahydropyranyl and pyrazinyl, which phenyl        or heterocycle is unsubstituted or substituted with 1-3        substituents each independently selected from:        -   (a) halo,        -   (b) —OR^(a),        -   (c) —C₁₋₆alkyl, which is unsubstituted or substituted with            1-6 halo,        -   (d) —C₃₋₆cycloalkyl, which is unsubstituted or substituted            with 1-6 halo,        -   (e) —CN, and        -   (f) —CO₂R^(a),    -   (4) —C₃₋₆cycloalkyl, which is unsubstituted or substituted with        1-6 halo;    -   or R^(b) and R^(c)and the nitrogen to which they are attached        join to form a 4-, 5-, or 6-membered ring optionally containing        an additional heteroatom selected from N, O, and S, wherein the        sulfur is optionally oxidized to the sulfone or sulfoxide, which        ring is unsubstituted or substituted with 1-4 substituents each        independently selected from:        -   (a) halo,        -   (b) —OR^(a), and        -   (c) —C₁₋₆alkyl, which is unsubstituted or substituted with            1-6 halo, and        -   (d) phenyl;-   R^(d) is independently selected from:    -   (1) C₁₋₆alkyl, which is unsubstituted or substituted with 1-4        substituents each independently selected from:        -   (a) halo,        -   (b) —OR^(a),        -   (c) —CO₂R^(a),        -   (d) —CN, and        -   (e) phenyl or heterocycle, wherein said heterocycle is            selected from pyridyl, pyrimidinyl, thienyl, pyridazinyl,            piperidinyl, azetidinyl, furanyl, piperazinyl, pyrrolidinyl,            morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and            pyrazinyl, which phenyl or heterocycle is unsubstituted or            substituted with 1-3 substituents each independently            selected from:            -   (i) halo,            -   (ii) —OR^(a),            -   (iii) —C₁₋₆alkyl, which is unsubstituted or substituted                with 1-6 halo, and            -   (iv) nitro,    -   (2) phenyl or heterocycle, wherein said heterocycle is selected        from pyridyl, pyrimidinyl, thienyl, pyridazinyl, piperidinyl,        azetidinyl, furanyl, piperazinyl, pyrrolidinyl, morpholinyl,        tetrahydrofuranyl, tetrahydropyranyl and pyrazinyl, which phenyl        or heterocycle is unsubstituted or substituted with 1-3        substituents each independently selected from:        -   (a) halo,        -   (a) —OR^(a),        -   (b) —C₁₋₆alkyl, which is unsubstituted or substituted with            1-6 halo,        -   (c) —C₃₋₆cycloalkyl, which is unsubstituted or substituted            with 1-6 halo        -   (d) —CN, and        -   (e) —CO₂R^(a), and    -   (3) -C₃₋₆cycloalkyl, which is unsubstituted or substituted with        1-6 halo;-   R^(e) and R^(f) are independently selected from:    -   (1) hydrogen,    -   (2) —C₁₋₄alkyl, which is unsubstituted or substituted with 1-6        halo,    -   (3) —OR^(a),    -   (4) —CN,    -   (5) halo,    -   (6) phenyl, and    -   (7) benzyl;    -   and R^(e) and R^(f) and the carbon atom or atoms to which they        are attached may join to form a 3-, 4-, 5-, or 6-membered ring        optionally containing a heteroatom selected from N, O, and S,        wherein the sulfur is optionally oxidized to the sulfone or        sulfoxide, which ring is unsubstituted or substituted with 1-4        substituents each independently selected from:        -   (a) halo,        -   (b) —OR^(a),        -   (c) —C₁₋₆alkyl, which is unsubstituted or substituted with            1-6 halo, and        -   (d) phenyl;-   R^(g) and R^(h) are independently selected from:    -   (1) —C₁₋₄alkyl, which is unsubstituted or substituted with 1-6        halo,    -   (2) —OR^(a),    -   (3) —C₃₋₆cycloalkyl, which is unsubstituted or substituted with        1-6 halo,    -   (4) phenyl, and    -   (5) benzyl;    -   and R^(g) and R^(h) and the silicon atom to which they are        attached may join to form a 3-, 4-, 5-, or 6-membered ring        optionally containing a heteroatom selected from N, O, and S,        wherein the sulfur is optionally oxidized to the sulfone or        sulfoxide, which ring is unsubstituted or substituted with 1-4        substituents each independently selected from:        -   (a) halo,        -   (b) —OR^(a),        -   (c) —C₁₋₄alkyl, which is unsubstituted or substituted with            1-3 halo, and        -   (d) phenyl;-   R^(i) and R^(j) are independently selected from:    -   (1) hydrogen,    -   (2) —C₁₋₄alkyl, which is unsubstituted or substituted with 1-6        halo,    -   (3) —OR^(a),    -   (4) halo,    -   (5) phenyl, and    -   (6) benzyl;-   q is 0, 1, or 2;    and pharmaceutically acceptable salts thereof and individual    enantiomers and diastereomers thereof.

In one embodiment of the present invention B is selected from the groupconsisting of:

which is unsubstituted or substituted with 1-7 substituents eachindependently selected from R¹, R², R³, R⁴, R¹⁰, and R¹¹, wherein T, U,V, W, X, R¹, R², R³, R⁴, R¹⁰, and R¹¹ are defined herein,and pharmaceutically acceptable salts thereof and individual enantiomersand diastereomers thereof.

In another embodiment of the present invention B is selected from thegroup consisting of:

which is unsubstituted or substituted with 1-7 substituents eachindependently selected from R¹, R², R³, R⁴, R¹⁰, and R¹¹, wherein R¹,R², R³, R⁴, R¹⁰, and R¹¹ are defined herein,and pharmaceutically acceptable salts thereof and individual enantiomersand diastereomers thereof.

In an embodiment of the present invention B is selected from2-oxobenzimidazolinyl, 2-oxopiperazinyl, 3-oxomorpholinyl and3-oxothiomorpholinyl.

In an embodiment of the present invention R¹, R², and R³ are eachindependently selected from:

-   -   (1) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-7        substituents each independently selected from:        -   (a) fluoro,        -   (b) hydroxy,        -   (c) —O—C₁₋₆ alkyl,        -   (d) —C₃₋₆ cycloalkyl,        -   (e) phenyl or heterocycle, wherein heterocycle is selected            from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,            piperidinyl, piperazinyl, pyrrolidinyl, oxazolyl, thiazolyl,            thienyl and morpholinyl, which phenyl or heterocycle is            unsubstituted or substituted with 1-5 substituents each            independently selected from: —C₁₋₆alkyl, —O—C₁₋₆alkyl, halo,            hydroxy, trifluoromethyl and —OCF₃,        -   (f) —CO₂R¹⁹        -   (g) —NR²⁰R^(21,)        -   (h) —SO₂R²²,        -   (i) —CONR^(20a)R^(21a),        -   (j) trifluoromethyl,        -   (k) —(NR^(20a))CO₂R¹⁹,        -   (l) —(NR¹⁹)(CO)NR^(20a)R^(21a), and        -   (m) —O—C₃₋₆cycloalkyl,    -   (2) —C₃₋₆cycloalkyl, which is unsubstituted or substituted with        1-7 substituents each independently selected from:        -   (a) fluoro,        -   (b) hydroxy,        -   (c) —O—C₁₋₆alkyl,        -   (d) trifluoromethyl, and        -   (e) phenyl, which is unsubstituted or substituted with 1-5            substituents each independently selected from: —C₁₋₆alkyl,            —O—C₁₋₆alkyl, halo, hydroxy and trifluoromethyl,    -   (3) phenyl or heterocycle, wherein heterocycle is selected from:        pyridyl, pyrimidinyl, pyrazinyl, thienyl, pyridazinyl,        pyrrolidinyl, azetidinyl, thiazolyl, isothiazolyl, oxazolyl,        isoxazolyl, imidazolyl, triazolyl, tetrazolyl, azepanyl,        benzimidazolyl, benzopyranyl, benzofuryl, benzothiazolyl,        benzoxazolyl, chromanyl, furyl, imidazolinyl, indolinyl,        indolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl,        isoindolinyl, tetrahydroisoquinolinyl, 2-oxopiperazinyl,        2-oxopiperidinyl, 2-oxopyrrolidinyl, pyrazolidinyl, pyrazolyl,        pyrrolyl, quinazolinyl, tetrahydrofuryl, thiazolinyl, purinyl,        naphthyridinyl, quinoxalinyl, 1,3-dioxolanyl, oxadiazolyl,        piperidinyl, tetrahydropyranyl, tetrahydrothienyl,        tetrahydrothiopyranyl, and morpholinyl, which phenyl or        heterocycle is unsubstituted or substituted with 1-5        substituents each independently selected from:        -   (a) —CF₃,        -   (b) halo,        -   (c) hydroxy,        -   (d) —O—CF₃,        -   (e) —C₃₋₆cycloalkyl,        -   (f) —CO₂R¹⁹,        -   (g) —(CO)R¹⁹,        -   (h) —CONR²⁰R²¹,        -   (i) oxo, and        -   (j) S(O)_(q)R²²,    -   (4) halo,    -   (5) oxo,    -   (6) hydroxy,    -   (7) —O—C₁₋₆alkyl which is unsubstituted or substituted with 1-5        halo,    -   (8) —CN,    -   (9) —CO₂R¹⁹,    -   (10) —NR²⁰R²¹,    -   (11) —SO₂R²²,    -   (12) —CONR^(20a)R^(21a),    -   (13) —SO₂NR^(20a)R^(21a), and    -   (14) hydrogen.

In an embodiment of the present invention R³ and R⁴ and the carbon atomto which they are attached join to form a ring selected fromcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,dioxolanyl, dioxanyl, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl,tetrahydrothiapyranyl, oxetanyl, thietanyl and tetrahydrothienyl,wherein the sulfur is optionally oxidized to the sulfone or sulfoxide,which ring is unsubstituted or substituted with 1-5 substituents eachindependently selected from:

-   -   (a) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-3        substituents each independently selected from:        -   (i) halo,        -   (ii) —OR^(a),        -   (iii) —C₃₋₆cycloalkyl,        -   (iv) —CO₂R^(a),        -   (v) —NR^(b)R^(c),        -   (vi) —S(O)_(q)R^(d),        -   (vii) —C(═O)NR^(b)R^(c), and        -   (viii) phenyl,    -   (b) phenyl or heterocycle, wherein heterocycle is selected from:        pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperdinyl,        piperazinyl, pyrrolidinyl, thienyl, morpholinyl, thiazolyl and        oxazolyl, wherein the phenyl or heterocycle is optionally fused        to the ring, and which phenyl or heterocycle is unsubstituted or        substituted with 1-5 substituents each independently selected        from:        -   (i) halo,        -   (ii) —CF₃        -   (iii) —OR^(a),        -   (iv) —CO₂R^(a),        -   (v) —O(C═O)R^(a),        -   (vi) —CN,        -   (vii) oxo, and        -   (viii) —C(═O)NR^(b)R^(c),    -   (c) halo,    -   (d) —CO₂R^(a),    -   (e) —C(═O)NR^(b)R^(c),    -   (1) —CN,    -   (g) —C(═O)R^(a), and    -   (h) oxo.

In an embodiment of the present invention X is selected from:

-   -   (1) —O—,    -   (2) —S(O)_(q)—,    -   (3) —N(R⁸)—,    -   (4) —(C═O)—,    -   (5) —C(R⁸)(R^(a))—,    -   (6) —C(N(R^(b))—SO₂R^(d))(R^(a))—,    -   (7) —C(N(R^(b))(C═O)R^(a))(R^(a))—,    -   (8) —C(N(R^(b))(C═O)OR^(a))(R^(a))—,    -   (9) —CR¹⁰R¹¹—,    -   (10) —N(R¹¹)—, and    -   (11) —CR³R⁴—.

In an embodiment of the present invention A¹ and A³ are independentlyselected from:

-   -   (1) —O—,    -   (2) —CR^(e)R^(f)—,    -   (3) —N(R⁷)—,    -   (4) —(C═O)—, and    -   (5) a bond.

In an embodiment of the present invention A¹ and A³ are a bond.

In an embodiment of the present invention A² and A⁴ are independentlyselected from:

-   -   (1) —O—,    -   (2) —CR^(e)R^(f)—,    -   (3) —N(R⁷)—, and    -   (4) —(C═O)—.

In an embodiment of the present invention A² and A⁴ are —CR^(e)R^(f)—,

In an embodiment of the present invention E^(a), E^(b), and E^(c) areeach independently selected from:

-   -   (1) —C(R⁵)═, and    -   (2) —N═;

In an embodiment of the present invention E^(a), E^(b), and E^(c) areeach independently selected from —C(R⁵)═.

In an embodiment of the present invention G¹ is selected from:

-   -   (1) a bond, and    -   (2) —CR^(e)R^(f)—.

In an embodiment of the present invention G¹ is a bond.

In an embodiment of the present invention G² is selected from:

-   -   (1) a bond,    -   (2) —CR^(e)R^(f)—,    -   (3) —C(R^(i))═C(R^(i))—, and    -   (4) —C≡C—.

In an embodiment of the present invention G² is a bond.

In an embodiment of the present invention G³ is selected from:

-   -   (1) a bond,    -   (2) —CR^(e)R^(f)—,    -   (2) —C(R^(i))═C(R^(i))—,    -   (4) —C═C—, and    -   (5) —(C═O)—.

In an embodiment of the present invention G⁴ is selected from:

-   -   (1) —CR^(e)R^(f)—,    -   (2) —N(R⁷)—,    -   (3) —O—,    -   (4) —S(O)_(q)—,    -   (5) —C(R^(i))═C(R^(i))—, and    -   (6) —C≡C—.

In an embodiment of the present invention R⁵ is selected from:

-   -   (1) hydrogen,    -   (2) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-7        substituents each independently selected from:        -   (a) halo,        -   (b) —OC₁₋₆alkyl, and        -   (c) phenyl,    -   (4) phenyl or heterocycle, wherein heterocycle is selected from:        pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperdinyl,        piperazinyl, pyrrolidinyl, thienyl, morpholinyl, thiazolyl and        oxazolyl, which phenyl or heterocycle is unsubstituted or        substituted with 1-5 substituents each independently selected        from:        -   (a) —C₁₋₄alkyl, which is unsubstituted or substituted with            1-5 fluoro,        -   (b) halo,        -   (c) —CN,        -   (d) hydroxy, and        -   (e) —O—C₁₋₆alkyl, which is unsubstituted or substituted with            1-6 fluoro,    -   (5) halo,    -   (6) hydroxy,    -   (7) —OC₁₋₆alkyl, which is unsubstituted or substituted with 1-5        halo,    -   (8) —CN, and    -   (9) —CO₂R¹⁹.

In an embodiment of the present invention R⁵ is selected from:

-   -   (1) hydrogen,    -   (2) —CF₃, and    -   (3) halo.

In an embodiment of the present invention R⁶ is selected from:

-   -   (1) hydrogen    -   (2) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-6        substituents each independently selected from:        -   (a) halo,        -   (b) —O—C₁₋₆alkyl, which is unsubstituted or substituted with            1-6 fluoro,        -   (c) —C₃₋₆cycloalkyl, which is unsubstituted or substituted            with 1-6 fluoro, and        -   (d) phenyl or heterocycle, wherein heterocycle is selected            from:            -   benzimidazolyl, furanyl, imidazolyl, indolyl,                morpholinyl, oxazolyl, oxadiazolyl, piperidyl,                piperazinyl, pyrazinyl, pyrazolidinyl, pyrazolyl,                pyridazinyl, pyridinyl, pyridyl, pyrimidinyl, pyrimidyl,                pyrrolidinyl, pyrrolyl, tetrahydrofuranyl,                tetrahydrofuryl, tetrazolyl, thiazolyl, thienyl,                isoxazolyl, tetrahydropyranyl, and triazolyl, which                phenyl or heterocycle is unsubstituted or substituted                with 1-3 substituents each independently selected from:                —C₁₋₆alkyl, —O—C₁₋₆alkyl, halo, hydroxy,                trifluoromethyl, —CN, and —OCF₃,    -   (3) phenyl or heterocycle, wherein heterocycle is selected from:        benzimidazolyl, furanyl, imidazolyl, indolyl, morpholinyl,        oxazolyl, oxadiazolyl, piperidyl, piperazinyl, pyrazinyl,        pyrazolidinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridyl,        pyrimidinyl, pyrimidyl, pyrrolidinyl, pyrrolyl,        tetrahydrofuranyl, tetrahydrofuryl, tetrazolyl, thiazolyl,        thienyl, isoxazolyl, tetrahydropyranyl, and triazolyl, which        phenyl or heterocycle is unsubstituted or substituted with 1-3        substituents each independently selected from:        -   (a) halo,        -   (b) —OR^(a),        -   (c) —CO₂R^(a),        -   (d) —C(═O)NR^(b)R^(c),        -   (e) —CN,        -   (f) —N(R^(b))C(═O)R^(a),        -   (g) —N(R^(b))SO₂R^(d), and        -   (h) —C₁₋₆alkyl, which is unsubstituted or substituted with            1-6 halo,    -   (4) —C₁₋₆cycloalkyl, which is unsubstituted or substituted with        1-5 substituents each independently selected from:        -   (a) halo,        -   (b) —CN, and        -   (c) —C₁₋₆alkyl, which is unsubstituted or substituted with            1-5 halo.

In an embodiment of the present invention R⁶ is phenyl or pyridyl.

In an embodiment of the present invention R⁷ is selected from:

-   -   (1) hydrogen,    -   (2) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-5        substituents each independently selected from:        -   (a) halo,        -   (b) —C₃₋₆cycloalkyl,        -   (c) —CF₃, and        -   (d) —O—R^(a),    -   (3) -C₃₋₆cycloalkyl.

In an embodiment of the present invention R⁷ is hydrogen or methyl.

In an embodiment of the present invention R⁸ is selected from:

-   -   (1) hydrogen,    -   (2) —C(═O)R^(a),    -   (3) —CO₂R^(a),    -   (4) —S(═O)R^(d),    -   (5) —SO₂R^(d),    -   (6) —C(═O)NR^(b)R^(c),    -   (7) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-5        halo,    -   (8) —C₃₋₆cycloalkyl, which is unsubstituted or substituted with        1-6 substituents each independently selected from:        -   (a) halo,        -   (b) —CN,        -   (c) OR^(a), and        -   (d) C₁₋₆alkyl, which is unsubstituted or substituted with            1-6 halo.

In an embodiment of the present invention R⁸ is hydrogen, methyl or—C(═O)R^(a).

In an embodiment of the present invention R⁴ and R⁸ and the atoms towhich they are attached join to form a 4-, 5-, 6- or 7-membered alkyl-or heteroalkyl-ring optionally containing an additional heteroatomselected from N, O, and S, wherein the sulfur is optionally oxidized tothe sulfone or sulfoxide, which ring is unsubstituted or substitutedwith 1-4 substituents each independently selected from:

-   -   (a) halo,    -   (b) phenyl, which is unsubstituted or substituted with 1-3        substituents each independently selected from: halo, OR^(a), CN,        and —C(═O)OR^(a),    -   (c) —OR^(a), and    -   (d) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-6        halo.

In an embodiment of the present invention R⁴ and R⁸ and the atoms towhich they are attached join to form a 4-, 5-, 6- or 7-membered alkyl-or heteroalkyl-ring optionally containing an additional heteroatomselected from N, O, and S, wherein the sulfur is optionally oxidized tothe sulfone or sulfoxide, which ring is unsubstituted or substitutedwith 1-4 substituents each independently selected from:

-   -   (a) halo, and    -   (b) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-6        halo.

In an embodiment of the present invention R¹⁰ is selected from:

-   -   (a) hydrogen, and    -   (b) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-6        fluoro;

In an embodiment of the present invention R¹⁰ is hydrogen.

In an embodiment of the present invention R¹¹ is independently selectedfrom the group consisting of:

-   -   phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl,        phenanthryl, anthryl, azepinyl, azepanyl, azetidinyl,        benzimidazolyl, benzisoxazolyl, benzofuranyl, benzofurazanyl,        benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl,        benzothienyl, benzoxazolyl, benzopyrazolyl, benzotriazolyl,        chromanyl, cinnolinyl, dibenzofuranyl, dihydrobenzofuryl,        dihydrobenzothienyl, dihydrobenzothiopyranyl,        dihydrobenzothiopyranyl sulfone, furyl, furanyl, imidazolidinyl,        imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl,        isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl,        morpholinyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl,        4-oxonaphthyridinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,        2-oxopyrrolidinyl, 2-oxopyridyl, 2-oxoquinolinyl, piperidyl,        piperazinyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl,        pyridinyl, pyridyl, pyrimidinyl, pyrimidyl, pyrrolidinyl,        pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl,        tetrahydrofuranyl, tetrahydrofuryl, tetrahydroimidazopyridinyl,        tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl,        thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl        sulfone, thiazolyl, thiazolinyl, thienofuryl, thienothienyl,        thienyl, triazolyl, isoxazolyl, tetrahydrothienyl,        tetrahydropyranyl, oxetanyl, tetrahydrothiapyranyl, and        thietanyl, where R¹¹ is unsubstituted or substituted with 1-5        substituents each independently selected from R¹², R¹³,        R^(14, R) ^(15a) and R^(15b), wherein R¹², R¹³, R¹⁴, R^(15a) a        and R^(15b) are defined herein;

In an embodiment of the present invention R¹¹ is independently selectedfrom the group consisting of:

-   -   phenyl, pyridyl, and thienyl, where R¹¹ is unsubstituted or        substituted with 1-5 substituents each independently selected        from R¹², R¹³, R¹⁴, R^(15a) and R^(15b), wherein R¹², R¹³, R¹⁴,        R^(15a) and R^(15b) are defined herein.

In an embodiment of the present invention R¹¹ is phenyl, which isunsubstituted or substituted with 1-5 substituents each independentlyselected from R¹², R¹³, R¹⁴, R^(15a) and R^(15b), wherein R¹², R¹³, R¹⁴,R^(15a) and R^(15b) are defined herein.

In an embodiment of the present invention R^(PG) is selected from:

-   -   (1) hydrogen,    -   (2) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-3        halo,    -   (3) —CH₂OR^(a), and    -   (4) —CH₂—O—CH₂CH₂Si(CH₃)₃;

In an embodiment of the present invention R^(PG) is methyl or hydrogen,

Another embodiment of the invention includes compounds of formula IA:

wherein A², A⁴, B, E^(a), E^(b), E^(c), G¹, G², G³, G⁴, and R⁶ aredefined herein;and pharmaceutically acceptable salts thereof and individual enantiomersand diastereomers thereof.

Another embodiment of the invention includes compounds of formula IB:

wherein B, E^(a), E^(b), E^(c), G¹, G², R⁶, and R⁷ are defined herein;and pharmaceutically acceptable salts thereof and individual enantiomersand diastereomers thereof.

Another embodiment of the invention includes compounds of formula IC:

wherein B, E^(a), E^(b), R⁶, and R⁷ are defined herein;and pharmaceutically acceptable salts thereof and individual enantiomersand diastereomers thereof.

Another embodiment of the invention includes compounds of formula ID:

wherein B and R⁶ are defined herein;and pharmaceutically acceptable salts thereof and individual enantiomersand diastereomers thereof.

The present invention is further directed to the exemplary compounds1-13, or a pharmaceutically acceptable salt thereof.

The invention is also directed to medicaments or pharmaceuticalcompositions for treating diseases or disorders in which CGRP isinvolved, such as migraine, which comprise a compound of formula (I), ora pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.

The invention is also directed to the use of a compound of formula (I)or a pharmaceutically acceptable salt thereof for treating diseases ordisorders in which CGRP is involved, such as migraine.

The invention is further directed to the use of a compound of theinvention or a pharmaceutically acceptable salt thereof for themanufacture of a medicament or a composition for treating diseases ordisorders in which CGRP is involved, such as migraine, by combining acompound of formula (I) with one or more pharmaceutically acceptablecarriers.

It is to be understood that where one or more of the above recitedstructures or substructures recite multiple substituents having the samedesignation each such variable may be the same or different from eachsimilarly designated variable. For example, R⁹ is recited multiple timesin certain configurations of formula I, and each instance of R⁹ informula I may independently be any of the substructures defined underR⁹. The invention is not limited to structures and substructures whereineach R⁹ must be the same for a given structural configuration. The sameis true with respect to any variable appearing multiple times in astructure or substructure.

The compounds of the present invention may contain one or moreasymmetric centers and can thus occur as racemates and racemic mixtures,single enantiomers, diastereomeric mixtures and individualdiastereomers. Additional asymmetric centers may be present dependingupon the nature of the various substituents on the molecule. Each suchasymmetric center will independently produce two optical isomers and itis intended that all of the possible optical isomers and diastereomersin mixtures and as pure or partially purified compounds are includedwithin the ambit of this invention. The present invention is meant tocomprehend all such isomeric forms of these compounds.

The independent syntheses of these diastereomers or theirchromatographic separations may be achieved as known in the art byappropriate modification of the methodology disclosed herein. Theirabsolute stereochemistry may be determined by the x-ray crystallographyof crystalline products or crystalline intermediates which arederivatized, if necessary, with a reagent containing an asymmetriccenter of known absolute configuration.

If desired, racemic mixtures of the compounds may be separated so thatthe individual enantiomers are isolated. The separation can be carriedout by methods well known in the art, such as the coupling of a racemicmixture of compounds to an enantiomerically pure compound to form adiastereomeric mixture, followed by separation of the individualdiastereomers by standard methods, such as fractional crystallization orchromatography. The coupling reaction is often the formation of saltsusing an enantiomerically pure acid or base. The diasteromericderivatives may then be converted to the pure enantiomers by cleavage ofthe added chiral residue. The racemic mixture of the compounds can alsobe separated directly by chromatographic methods utilizing chiralstationary phases, which methods are well known in the art.

Alternatively, any enantiomer of a compound may be obtained bystereoselective synthesis using optically pure starting materials orreagents of known configuration by methods well known in the art.

Some of the compounds described herein contain olefinic double bonds,and unless specified otherwise, are meant to include both E and Zgeometric isomers.

The present invention includes compounds of formula I wherein on or morehydrogen atoms are replaced by deuterium. Tautomers of compounds definedin Formula I are also included within the scope of the presentinvention. For example, compounds including carbonyl —CH₂C(O)— groups(keto forms) may undergo tautomerism to form hydroxyl —CH═C(OH)— groups(enol forms). Both keto and enol forms are included within the scope ofthe present invention.

As appreciated by those of skill in the art, halo or halogen as usedherein are intended to include chloro, fluoro, bromo and iodo.

As used herein, “alkyl” is intended to mean linear or branchedstructures having no carbon-to-carbon double or triple bonds. ThusC₁₋₆alkyl is defined to identify the group as having 1, 2, 3, 4, 5 or 6carbons in a linear or branched arrangement, such that C _(—)6alkylspecifically includes, but is not limited to, methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, tert-butyl, pentyl and hexyl.“Cycloalkyl” is an alkyl, part or all of which which forms a ring ofthree or more atoms. C₀ or C₀alkyl is defined to identify the presenceof a direct covalent bond.

As used herein, “aryl” is intended to mean any stable monocyclic orbicyclic carbon ring of up to 7 members in each ring, wherein at leastone ring is aromatic. Examples of such aryl elements include phenyl,napthyl, tetrahydronapthyl, indanyl, or biphenyl.

The term “heterocycle” or “heterocyclic”, as used herein except wherenoted, represents a stable 5- to 7-membered monocyclic- or stable 8- to11-membered bicyclic heterocyclic ring system which is either saturatedor unsaturated, and which consists of carbon atoms and from one to sixheteroatoms selected from the group consisting of N, O, S, P and Si, andwherein the nitrogen, sulfur and phosphorus heteroatoms may optionallybe oxidized, and the nitrogen heteroatom may optionally be quaternized,and including any bicycle group in which any of the above-definedheterocyclic rings is fused to a benzene ring. The heterocyclic ring maybe attached at any heteroatom or carbon atom which results in thecreation of a stable structure.

When a heterocyclic group as defined herein is substituted, thesubstituent may be bonded to a ring carbon atom of the heterocyclicgroup, or on a ring heteroatom (i.e., a nitrogen, oxygen or sulfur),which has a valence which permits substitution. Similarly, when aheterocyclic group is defined as a substituent herein, the point ofattachment may be at a ring carbon atom of the heterocyclic group, or ona ring heteroatom (i.e., a nitrogen, oxygen or sulfur), which has avalence which permits attachment.

The term “alkoxy,” as in C₁-C₆ alkoxy, includes alkoxy groups of from 1to 6 carbon atoms of a straight, branched and cyclic configuration.Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy,cyclohexyloxy and the like.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativeswherein the parent compound is modified by making acid or base saltsthereof. Examples of pharmaceutically acceptable salts include, but arenot limited to, mineral or organic acid salts of basic residues such asamines; alkali or organic salts of acidic residues such as carboxylicacids; and the like. The pharmaceutically acceptable salts include theconventional non-toxic salts or the quaternary ammonium salts of theparent compound formed, for example, from non-toxic inorganic or organicacids. For example, such conventional non-toxic salts include thosederived from inorganic acids such as hydrochloric, hydrobromic,sulfuric, sulfamic, phosphoric, nitric and the like; and the saltsprepared from organic acids such as acetic, propionic, succinic,glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic,maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic,sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic,ethane disulfonic, oxalic, isethionic, and the like.

When the compound of the present invention is basic, salts may beprepared from pharmaceutically acceptable non-toxic acids, includinginorganic and organic acids. Such acids include acetic, benzenesulfonic,benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic,glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic,phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, andthe like. In one aspect of the invention the salts are citric,hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, andtartaric acids. It will be understood that, as used herein, referencesto the compounds of Formula I are meant to also include thepharmaceutically acceptable salts.

The subject compounds are useful in a method of antagonism of CGRPreceptors in a patient such as a mammal in need of such antagonismcomprising the administration of an effective amount of the compound.The present invention is directed to the use of the compounds disclosedherein as antagonists of CGRP receptors. In addition to primates,especially humans, a variety of other mammals can be treated accordingto the method of the present invention.

Another embodiment of the present invention is directed to a method forthe treatment, control, amelioration, or reduction of risk of a diseaseor disorder in which the CGRP receptor is involved in a patient thatcomprises administering to the patient a therapeutically effectiveamount of a compound that is an antagonist of CGRP receptors.

The present invention is further directed to a method for themanufacture of a medicament for antagonism of CORP receptors activity inhumans and animals comprising combining a compound of the presentinvention with a pharmaceutical carrier or diluent.

The subject treated in the present methods is generally a mammal, forexample a human being, male or female, in whom antagonism of CGRPreceptor activity is desired. The term “therapeutically effectiveamount” means the amount of the subject compound that will elicit thebiological or medical response of a tissue, system, animal or human thatis being sought by the researcher, veterinarian, medical doctor or otherclinician. As used herein, the term “treatment” refers both to thetreatment and to the prevention or prophylactic therapy of the mentionedconditions, particularly in a patient who is predisposed to such diseaseor disorder.

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts. Such term inrelation to pharmaceutical composition, is intended to encompass aproduct comprising the active ingredient(s), and the inert ingredient(s)that make up the carrier, as well as any product which results, directlyor indirectly, from combination, complexation or aggregation of any twoor more of the ingredients, or from dissociation of one or more of theingredients, or from other types of reactions or interactions of one ormore of the ingredients. Accordingly, the pharmaceutical compositions ofthe present invention encompass any composition made by admixing acompound of the present invention and a pharmaceutically acceptablecarrier. By “pharmaceutically acceptable” it is meant the carrier,diluent or excipient must be compatible with the other ingredients ofthe formulation and not deleterious to the recipient thereof.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds of this invention which arereadily convertible in vivo into the required compound. Thus, in themethods of treatment of the present invention, the terms “administrationof” or “administering a” compound shall encompass the treatment of thevarious conditions described with the compound specifically disclosed orwith a compound which may not be specifically disclosed, but whichconverts to the specified compound in vivo after administration to thepatient. Conventional procedures for the selection and preparation ofsuitable prodrug derivatives are described, for example, in “Design ofProdrugs,” ed. H. Bundgaard, Elsevier, 1985. Metabolites of thesecompounds include active species produced upon introduction of compoundsof this invention into the biological milieu.

The ability of the compounds of the present invention to act as CORPantagonists makes them useful pharmacological agents for disorders thatinvolve CGRP in humans and animals, but particularly in humans.

The compounds of the present invention have utility in treating,preventing, ameliorating, controlling or reducing the risk of one ormore of the following conditions or diseases: headache; migraine;cluster headache; chronic tension type headache; pain; chronic pain;neurogenic inflammation and inflammatory pain; neuropathic pain; eyepain; tooth pain; diabetes; non-insulin dependent diabetes mellitus;vascular disorders; inflammation; arthritis; bronchial hyperreactivity,asthma; shock; sepsis; opiate withdrawal syndrome; morphine tolerance;hot flashes in men and women; allergic dermatitis; psoriasis;encephalitis; brain trauma; epilepsy; neurodegenerative diseases; skindiseases; neurogenic cutaneous redness, skin rosaceousness and erythema;inflammatory bowel disease, irritable bowel syndrome, cystitis; andother conditions that may be treated or prevented by antagonism of CORPreceptors. Of particular importance is the acute or prophylactictreatment of headache, including migraine and cluster headache.

The compounds of the present invention may be used in combination withone or more other drugs in the treatment, prevention, control,amelioration, or reduction of risk of diseases or conditions for whichcompounds of Formula I or the other drugs may have utility, where thecombination of the drugs together are safer or more effective thaneither drug alone. Such other drug(s) may be administered, by a routeand in an amount commonly used therefor, contemporaneously orsequentially with a compound of Formula I. When a compound of Formula Ior II is used contemporaneously with one or more other drugs, apharmaceutical composition in unit dosage form containing such otherdrugs and the compound of Formula I is preferred. However, thecombination therapy may also include therapies in which the compound ofFormula I and one or more other drugs are administered on differentoverlapping schedules. It is also contemplated that when used incombination with one or more other active ingredients, the compounds ofthe present invention and the other active ingredients may be used inlower doses than when each is used singly. Accordingly, thepharmaceutical compositions of the present invention include those thatcontain one or more other active ingredients, in addition to a compoundof Formula I.

For example, the present compounds may be used in conjunction with an ananti-migraine agent, such as ergotamine and dihydroergotamine, or otherserotonin agonists, especially a 5-HT^(1B/1D) agonist, for examplesumatriptan, naratriptan, zolmitriptan, eletriptan, almotriptan,frovatriptan, donitriptan, and rizatriptan, a 5-HT_(1D) agonist such asPNU-142633 and a 5-HT_(1F) agonist such as LY334370; a cyclooxygenaseinhibitor, such as a selective cyclooxygenase-2 inhibitor, for examplerofecoxib, etoricoxib, celecoxib, valdecoxib or paracoxib; anon-steroidal anti-inflammatory agent or a cytokine-suppressinganti-inflammatory agent, for example with a compound such as ibuprofen,ketoprofen, fenoprofen, naproxen, indomethacin, sulindac, meloxicam,piroxicam, tenoxicam, lornoxicam, ketorolac, etodolac, mefenamic acid,meclofenamic acid, flufenamic acid, tolfenamic acid, diclofenac,oxaprozin, apazone, nimesulide, nabumetone, tenidap, etanercept,tolmetin, phenylbutazone, oxyphenbutazone, diflunisal, salsalate,olsalazine or sulfasalazine and the like; or glucocorticoids. Similarly,the instant compounds may be administered with an analgesic such asaspirin, acetaminophen, phenacetin, fentanyl, sufentanil, methadone,acetyl methadol, buprenorphine or morphine.

Additionally, the present compounds may be used in conjunction with aninterleukin inhibitor, such as an interleukin-1 inhibitor; an NK-1receptor antagonist, for example aprepitant; an NMDA antagonist; an NR2Bantagonist; a bradykinin-1 receptor antagonist; an adenosine A1 receptoragonist; a sodium channel blocker, for example lamotrigine; an opiateagonist such as levomethadyl acetate or methadyl acetate; a lipoxygenaseinhibitor, such as an inhibitor of 5-lipoxygenase; an alpha receptorantagonist, for example indoramin; an alpha receptor agonist; avanilloid receptor antagonist; a renin inhibitor; a granzyme Binhibitor; a substance P antagonist; an endothelin antagonist; anorepinephrin precursor; anti-anxiety agents such as diazepam,alprazolam, chlordiazepoxide and chlorazepate; serotonin 5HT₂ receptorantagonists; opiod agonists such as codeine, hydrocodone, tramadol,dextropropoxyphene and febtanyl; an mGluR5 agonist, antagonist orpotentiator; a GABA A receptor modulator, for example acamprosatecalcium; nicotinic antagonists or agonists including nicotine;muscarinic agonists or antagonists; a selective serotonin reuptakeinhibitor, for example fluoxetine, paroxetine, sertraline, duloxetine,escitalopram, or citalopram; an antidepressant, for exampleamitriptyline, nortriptyline, clomipramine, imipramine, venlafaxine,doxepin, protriptyline, desipramine, trimipramine, or imipramine; aleukotriene antagonist, for example montelukast or zafirlukast; aninhibitor of nitric oxide or an inhibitor of the synthesis of nitricoxide.

Also, the present compounds may be used in conjunction with gap junctioninhibitors; neuronal calcium channel blockers such as civamide; AMPA/KAantagonists such as LY293558; sigma receptor agonists; and vitamin B2.

Also, the present compounds may be used in conjunction with ergotalkaloids other than ergotamine and dihydroergotamine, for exampleergonovine, ergonovine, methylergonovine, metergoline, ergoloidmesylates, dihydroergocornine, dihydroergocristine, dihydroergocryptine,dihydro-α-ergocryptine, dihydro-β-ergocryptine, ergotoxine, ergocornine,ergocristine, ergocryptine, α-ergocryptine, β-ergocryptine, ergosine,ergostane, bromocriptine, or methysergide.

Additionally, the present compounds may be used in conjunction with abeta-adrenergic antagonist such as timolol, propanolol, atenolol,metoprolol or nadolol, and the like; a MAO inhibitor, for examplephenelzine; a calcium channel blocker, for example flunarizine,diltiazem, amlodipine, felodipine, nisolipine, isradipine, nimodipine,lomerizine, verapamil, nifedipine, or prochlorperazine; neurolepticssuch as olanzapine, droperidol, prochlorperazine, chlorpromazine andquetiapine; an anticonvulsant such as topiramate, zonisamide,tonabersat, carabersat, levetiracetam, lamotrigine, tiagabine,gabapentin, pregabalin or divalproex sodium; an anti-hypertensive suchas an angiotensin H antagonist, for example losartan, irbesartin,valsartan, eprosartan, telmisartan, olmesartan, medoxomil, candesartanand candesartan cilexetil, an angiotensin I antagonist, an angiotensinconverting enzyme inhibitor such as lisinopril, enalapril, captopril,benazepril, quinapril, perindopril, ramipril and trandolapril; orbotulinum toxin type A or B.

The present compounds may be used in conjunction with a potentiator suchas caffeine, an H2-antagonist, simethicone, aluminum or magnesiumhydroxide; a decongestant such as oxymetazoline, epinephrine,naphazoline, xylometazoline, propylhexedrine, or levo-desoxy-ephedrine;an antitussive such as caramiphen, carbetapentane, or dextromethorphan;a diuretic; a prokinetic agent such as metoclopramide or domperidone; asedating or non-sedating antihistamine such as acrivastine, azatadine,bromodiphenhydramine, brompheniramine, carbinoxamine, chlorpheniramine,clemastine, dexbrompheniramine, dexchlorpheniramine, diphenhydramine,doxylamine, loratadine, phenindamine, pheniramine, phenyltoloxamine,promethazine, pyrilamine, terfenadine, triprolidine, phenylephrine,phenylpropanolamine, or pseudoephedrine. The present compounds also maybe used in conjunction with anti-emetics.

In a particularly preferred embodiment the present compounds are used inconjunction with an anti-migraine agent, such as: ergotamine ordihydroergotamine; a 5-HT₁ agonist, especially a 5-HT_(1B/1D) agonist,in particular, sumatriptan, naratriptan, zolmitriptan, eletriptan,almotriptan, frovatriptan, donitriptan, avitriptan and rizatriptan, andother serotonin agonists; and a cyclooxygenase inhibitor, such as aselective cyclooxygenase-2 inhibitor, in particular, rofecoxib,etoricoxib, celecoxib, valdecoxib or paracoxib.

The above combinations include combinations of a compound of the presentinvention not only with one other active compound, but also with two ormore other active compounds. Likewise, compounds of the presentinvention may be used in combination with other drugs that are used inthe prevention, treatment, control, amelioration, or reduction of riskof the diseases or conditions for which compounds of the presentinvention are useful. Such other drugs may be administered, by a routeand in an amount commonly used therefore, contemporaneously orsequentially with a compound of the present invention. When a compoundof the present invention is used contemporaneously with one or moreother drugs, a pharmaceutical composition containing such other drugs inaddition to the compound of the present invention is preferred.Accordingly, the pharmaceutical compositions of the present inventioninclude those that also contain one or more other active ingredients, inaddition to a compound of the present invention.

The weight ratio of the compound of the compound of the presentinvention to the other active ingredient(s) may be varied and willdepend upon the effective dose of each ingredient. Generally, aneffective dose of each will be used. Thus, for example, when a compoundof the present invention is combined with another agent, the weightratio of the compound of the present invention to the other agent willgenerally range from about 1000:1 to about 1:1000, or from about 200:1to about 1:200. Combinations of a compound of the present invention andother active ingredients will generally also be within theaforementioned range, but in each case, an effective dose of each activeingredient should be used.

In such combinations the compound of the present invention and otheractive agents may be administered separately or in conjunction. Inaddition, the administration of one element may be prior to, concurrentto, or subsequent to the administration of other agent(s), and via thesame or different routes of administration.

The compounds of the present invention may be administered by oral,parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV,intracisternal injection or infusion, subcutaneous injection, orimplant), by inhalation spray, nasal, vaginal, rectal, sublingual, ortopical routes of administration and may be formulated, alone ortogether, in suitable dosage unit formulations containing conventionalnon-toxic pharmaceutically acceptable carriers, adjuvants and vehiclesappropriate for each route of administration. In addition to thetreatment of warm-blooded animals the compounds of the invention areeffective for use in humans.

The pharmaceutical compositions for the administration of the compoundsof this invention may conveniently be presented in dosage unit form andmay be prepared by any of the methods well known in the art of pharmacy.All methods include the step of bringing the active ingredient intoassociation with the carrier which constitutes one or more accessoryingredients. In general, the pharmaceutical compositions are prepared byuniformly and intimately bringing the active ingredient into associationwith a liquid carrier or a finely divided solid carrier or both, andthen, if necessary, shaping the product into the desired formulation. Inthe pharmaceutical composition the active compound is included in anamount sufficient to produce the desired effect upon the process orcondition of diseases. As used herein, the term “composition” isintended to encompass a product comprising the specified ingredients inthe specified amounts, as well as any product which results, directly orindirectly, from combination of the specified ingredients in thespecified amounts.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, solutions, hard or soft capsules, or syrups or elixirs.Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia; and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed. They may also becoated by the techniques described in the U.S. Pat. Nos. 4,256,108;4,160,452; and 4,265,874 to form osmotic therapeutic tablets for controlrelease. Oral tablets may also be formulated for immediate release, suchas fast melt tablets or wafers, rapid dissolve tablets or fast dissolvefilms.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butane diol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of the present invention may also be administered in theform of suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

For topical use, creams, ointments, jellies, solutions or suspensionsand the like, containing the compounds of the present invention areemployed. Similarly, transdermal patches may also be used for topicaladministration.

The pharmaceutical composition and method of the present invention mayfurther comprise other therapeutically active compounds as noted hereinwhich are usually applied in the treatment of the above mentionedpathological conditions.

In the treatment, prevention, control, amelioration, or reduction ofrisk of conditions which require antagonism of CGRP receptor activity anappropriate dosage level will generally be about 0.01 to 500 mg per kgpatient body weight per day which can be administered in single ormultiple doses. A suitable dosage level may be about 0.01 to 250 mg/kgper day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg perday. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to50 mg/kg per day. For oral administration, the compositions are may beprovided in the form of tablets containing 1.0 to 1000 milligrams of theactive ingredient, particularly 1.0, 5.0, 10.0, 15.0. 20.0, 25.0, 50.0,75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0,800.0, 900.0, and 1000.0 milligrams of the active ingredient for thesymptomatic adjustment of the dosage to the patient to be treated. Thecompounds may be administered on a regimen of 1 to 4 times per day, ormay be administered once or twice per day.

When treating, preventing, controlling, ameliorating, or reducing therisk of headache, migraine, cluster headache, or other diseases forwhich compounds of the present invention are indicated, generallysatisfactory results are obtained when the compounds of the presentinvention are administered at a daily dosage of from about 0.1 milligramto about 100 milligram per kilogram of animal body weight, given as asingle daily dose or in divided doses two to six times a day, or insustained release form. For most large mammals, the total daily dosageis from about 1.0 milligrams to about 1000 milligrams, or from about 1milligrams to about 50 milligrams. In the case of a 70 kg adult human,the total daily dose will generally be from about 7 milligrams to about350 milligrams. This dosage regimen may be adjusted to provide theoptimal therapeutic response.

It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the host undergoing therapy.

Several methods for preparing the compounds of this invention areillustrated in the following Schemes and Examples. Starting materialsare made according to procedures known in the art or as illustratedherein.

The compounds of the present invention can be prepared readily accordingto the following Schemes and specific examples, or modificationsthereof, using readily available starting materials, reagents andconventional synthesis procedures. In these reactions, it is alsopossible to make use of variants which are themselves known to those ofordinary skill in this art but are not mentioned in greater detail. Thegeneral procedures for making the compounds claimed in this inventioncan be readily understood and appreciated by one skilled in the art fromviewing the following Schemes.

Scheme 1 illustrates a general strategy for the synthesis of thecompounds of the present invention via coupling of carboxylic acid Awith amine B to give amide C. Standard coupling conditions, such as EDCand HOBT with DIEA as base and DMF as solvent, may be successfullyemployed in this reaction. Other standard coupling conditions may beemployed in the synthesis of such amides, including use of analternative coupling reagent such as BOP, HATU or PyCLU, or activationof the carboxylic acid as an acid anhydride or acid chloride. In somecases, various protecting group strategies familiar to one skilled inthe art of organic synthesis may be employed to allow preparation of aparticular compound of the present invention.

Most of the acids A used to make the compounds of the present inventionare readily available. They may be obtained from commercial sources orsynthesized by methodology familiar to those skilled in the art and asdescribed in the chemical literature. Many of the acids A of interestare also described in Wood et al WO 2008/020902 and Bell et al, U.S.Pat. No. 7,202,251.

The synthesis of amine intermediates may be conducted as described inSchemes 2-3. Amine intermediates bearing a variety of substituents maybe prepared by employing appropriately substituted starting materials orby derivatization of any intermediates and/or final products as desiredby methods known in the art.

The synthesis of a representative spiroimidazolone aniline (5) isillustrated in Scheme 2. The commercially available indane (1) can bealternately protected as the CBZ carbamate (2). Conversion of thecarboxylic acid to the primary amide followed by Boc deprotection canproduce the α-aminoamide 3, which cyclizes to the imidazolone 4 aftertreatment with (trimethoxymethyl)benzene and heating in toluene. Thereaction of aldehyde 3 with orthoesters other than(trimethoxymethyl)benzene may be used to provide a variety ofsubstituted imidazolones 4. The intermediate 4 may be deprotected toprovide aniline 5 using a variety of well known methodologies, such ascatalytic hydrogenation. Those skilled in the art of organic synthesiswill recognize that straightforward modifications of this methodologymay be used to access other spiroimidazolone intermediates.Additionally, use of an alternative starting material to the indane 1may be used to provide different products, such as tetralin-basedspiroimidazolones.

In Scheme 3, an alternate route to the synthesis of a spiroimidazoloneintermediate is shown. Treatment of hydantoin 6 (Bell et al. (2006)Bioorg. Med. Chem. Lett. 16, 6165) with Boc anhydride followed byhydrolysis with NaOH leads to indanyl amino acid 7. Protection of theprimary amine, followed by conversion of the carboxylic acid to theprimary amide and subsequent deprotection may produce intermediate 8. Avariety of ways may be used to form the spiroimidazolone ring (9), oneof which is via amide coupling to a carboxylic acid, followed by basecatalyzed cyclization. Another method may be reaction with an acidchloride, followed by base catalyzed cyclization. The nitro intermediate9 may be reduced to provide aniline 5 using a variety of well knownmethodologies, such as catalytic hydrogenation. Alternate reductionconditions using tin or iron may also be used for the conversion of 9 to5.

In some cases the final product may be further modified, for example, bymanipulation of substituents. These manipulations may include, but arenot limited to, reduction, oxidation, alkylation, acylation, andhydrolysis reactions which are commonly known to those skilled in theart.

In some cases the order of carrying out the foregoing reaction schemesmay be varied to facilitate the reaction or to avoid unwanted reactionproducts. The following examples are provided so that the inventionmight be more fully understood. These examples are illustrative only andshould not be construed as limiting the invention in any way.

Intermediate 1

(±)-Benzyl[2-amino-2-(aminocarbonyl)-2,3-dihydro-1H-inden-5-yl]carbamateStep A. (±)-5-Amino-2-[(text-butoxycarbonyl)amino]indane-2-carboxylicacid

Diethylamine (2.01 mL, 19.4 mmol) was added to a solution of(±)-2-[(tert-butoxycarbonyl)amino]-5-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}indane-2-carboxylicacid (1.00 g, 1.94 mmol) in THF (5 mL) at ambient temperature and themixture was stirred for 3 h. The reaction mixture was poured onto INNaOH (30 mL) and extracted with EtOAc (3×30 mL). The aqueous layer wasacidified with concentrated HCl and extracted with CH₂Cl₂ (3×30 mL) andthe combined CH₂Cl₂ layers were dried over Na₂SO₄, filtered,concentrated and dried under high vacuum to give the title compound. MS:m/z=293 (M+1).

Step B.(±)-5-{[(Benzyloxy)carbonyl]amino}-2-[(tert-butoxycarbonyl)amino]indane-2-carboxylicacid

To a solution of(±)-5-amino-2-[(tent-butoxycarbonyl)amino]indane-2-carboxylic acid fromStep A (568 mg, 1.94 mmol) in dioxane (16 mL) and water (4 mL) was addedsodium carbonate (412 mg, 3.89 mmol) and1-{[(benzyloxy)carbonyl]oxy}pyrrolidine-2,5-dione (533 mg, 2.14 mmol).The reaction was stirred at ambient temperature for 16 h, then pouredonto saturated NH₄Cl (30 mL) and extracted with EtOAc (3×30 mL). Thecombined organic layers were dried over Na₂SO₄, filtered, concentratedand dried under high vacuum to give the title compound. MS: m/z=449(M+Na).

Step C. (±)-Benzyltert-butyl[2-(aminocarbonyl)-2,3-dihydro-1H-indene-2,5-diyl]biscarbamate

A solution of(±)-5-{[(benzyloxy)carbonyl]amino)-2-tert-butoxycarbonyl)amino]indane-2-carboxylicacid from Step B (829 mg, 1.94 mmol), ammonium chloride (208 mg, 3.89mmol), pyBOP (1.52 g, 2.92 mmol), and DIEA (1.35 mL, 7.78 mmol) in DMF(3 mL) was stirred at ambient temperature for 16 h. The reaction mixturewas poured onto saturated NaHCO₃ (20 mL) and extracted with CH₂Cl₂ (3×20mL). The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The crude product was purified bysilica gel chromatography, eluting with a gradient ofCH₂Cl₂:MeOH:NH₄OH—100:0:0 to 90:9:1, to give the title compound, MS:m/z=426 (M+1).

Step D.(±)-Benzyl[2-amino-2-(aminocarbonyl)-2,3-dihydro-1H-inden-5-yl]carbamate

A solution of (±)-benzyltent-butyl[2-(aminocarbonyl)-2,3-dihydro-1H/-indene-2,5-diyl]biscarbamatefrom Step C (670 mg, 1.58 mmol) in CH₂Cl₂ (5 mL) and TFA (1 mL) wasstirred for 16 h. The reaction mixture was poured onto saturated NaHCO₃(10 mL) and extracted with CH₂Cl₂ (3×10 mL). The combined organic layerswere dried over Na₂SO₄, filtered, concentrated and dried under highvacuum to give the title compound. MS: m/z=326 (M+1).

Intermediate 2

(±)-5′-Amino-2-phenyl-1′,3′-dihydrospiro[imidazole-4,2′-inden]-5(1H)-oneStep A.(±)-Benzyl(5-oxo-2-phenyl-1,1′,3′,5-tetrahydrospiro[imidazole-4,2′-inden]-5′-yl)carbamate

A solution of(±)-benzyl[2-amino-2-(aminocarbonyl)-2,3-dihydro-1H-inden-5-yl]carbamate(described in Intermediate 1, 35.0 mg, 0.108 mmol) and(trimethoxymethyl)benzene (0.022 mL, 0.129 mmol) in toluene (5 mL) washeated at reflux for 7.5 h. The reaction mixture was concentrated underreduced pressure. The crude product was dissolved in DMSO (1 mL) andpurified by HPLC using a reversed phase C18 column and eluting with agradient of H₂O:CH₃CN:CF₃CO₂H—90:10:0.1 to 5:95:0.1. The pure,product-containing fractions were combined and concentrated to give thetitle compound. MS: m/z=412 (M+1).

Step B.(±)-5′-Amino-2-phenyl-1′,3′-dihydrospiro[imidazole-4,2′-inden]-5(1H)-one

To a solution of (±)-benzyl(5-oxo-2-phenyl-1,1′,3′,5-tetrahydrospiro[imidazole-4,2′-inden]-5′-yl)carbamatefrom Step A (568 mg, 1.94 mmol) in degassed MeOH (2 mL) was added 10%palladium on carbon (5 mg). The suspension was placed under a hydrogenballoon for 3 h, then filtered through a pad of Celite, concentrated,and dried under high vacuum to give the title compound. MS: m/z=278(M+1).

Intermediate 3

(±)-2-Amino-5-nitroindane-2-carboxamide Step A. (±)-Di-tert-butyl5′-nitro-2,5-dioxo-1′,3′-dihydro-1H,3/H-spiro[imidazolidine-4,2-indene]-1,3-dicarboxylate

A solution of(±)-5′-nitro-1′,3′-dihydro-2H,5H-spiro[imidazolidine-4,2′-indene]-2,5-dione(1.20 g, 4.85 mmol, described in Bell et al. (2006) Bioorg. Med. Chem.Lett. 16, 6165), di-tert-butyl dicarbonate (5.30 g, 24.3 mmol), TEA (540mg, 5.34 mmol), and DMAP (12.0 mg, 0.097 mmol) in DME (29 mL) wasstirred at ambient temperature for 16 h. The reaction mixture wasconcentrated in vacuo and the crude product dissolved in CH₂Cl₂ (50 mL).The organic layer was washed with 10% HCl (20 mL), saturated Na₂CO₃ (20mL), brine (20 mL), dried over Na₂SO₄, filtered, concentrated and driedunder high vacuum to give the title compound. MS: m/z=448 (M+1).

Step B. (±)-2-Amino-5-nitroindane-2-carboxylic acid

To a solution of (±)-di-tert-butyl5′-nitro-2,5-dioxo-1′,3′-dihydro-1H,3H-spiro[imidazolidine-4,2′-indene]-1,3-dicarboxylatefrom Step A (2.17 g, 4.85 mmol) in DME (16 mL) was added 1N NaOH (43.7mL, 43.7 mmol) and the reaction mixture was stirred at ambienttemperature for 20 h. The reaction mixture was diluted with water (20mL) and Et₂O (20 mL). The suspension was filtered and the layersseparated. The aqueous layer was further washed with Et₂O (20 mL). Theaqueous layer was concentrated to a volume of 30 mL and purified by HPLCusing a reversed phase C18 column and eluting with a gradient ofH₂O:CH₃CN:CF₃CO₂H—90:10:0.1 to 5:95:0.1. The pure, product-containingfractions were combined and concentrated to give the title compound asthe trifluoroacetate salt. MS: m/z=223 (M+1).

Step C. (±)-2-[(tert-Butoxycarbonyl)amino]-5-nitroindane-2-carboxylicacid

A solution of (±)-2-amino-5-nitroindane-2-carboxylic acid from Step B(490 mg, 1.46 mmol), di-tent-butyl dicarbonate (318 mg, 1.46 mmol), andTEA (0.609 mL, 4.37 mmol), was stirred in DME (20 mL) at ambienttemperature for 24 h. At 20 h, additional di-tent-butyl dicarbonate (100mg) was added. The reaction mixture was poured onto 10% HCl (30 mL) andextracted with EtOAc (3×20 mL). The combined organic layers were driedover Na₂SO₄, filtered, concentrated and dried under high vacuum to givethe title compound. MS: m/z=323 (M+1).

Step D.(±)-tert-Butyl[2-(aminocarbonyl)-5-nitro-2,3-dihydro-1H-inden-2-yl]carbamate

A solution of(±)-2-[(tent-butoxycarbonyl)amino]-5-nitroindane-2-carboxylic acid fromStep C (470 mg, 1.46 mmol), ammonium chloride (156 mg, 2.92 mmol), EDC(419 mg, 2.19 mmol), HORT (335 mg, 2.19 mmol), and DIEA (1.27 mL, 7.29mmol) in DMF (5 mL) was stirred at ambient temperature for 16 h. Thereaction mixture was poured onto saturated NaHCO₃ (20 mL) and extractedwith CH₂Cl₂ (3×20 mL). The combined organic layers were dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The crudeproduct was purified by silica gel chromatography, eluting with agradient of CH₂Cl₂:MeOH:NH₄OH—100:0:0 to 90:9:1, to give the titlecompound. MS: m/z=322 (M+1).

Step E. (±)-2-Amino-5-nitroindane-2-carboxamide

To a solution of(±)-tert-butyl[2-(aminocarbonyl)-5-nitro-2,3-dihydro-1H-inden-2-yl]carbamatefrom Step D (113 mg, 0.352 mmol) in EtOAc (5 mL) was bubbled HCl_((g))for 10 min. The reaction mixture was concentrated under reducedpressure. The crude product was dissolved in DMSO (1 mL) and purified byHPLC using a reversed phase C18 column and eluting with a gradient ofH₂O:CH₃CN:CF₃CO₂H—90:10:0.1 to 5:95:0.1. The pure, product-containingfractions were combined and concentrated to give the title compound asthe trifluoroacetate salt. MS: m/z=258 (M+1).

Intermediate 4

Step A.(±)-5′-Nitro-2-propyl-1′,3′-dihydrospiro[imidazole-4,2′-inden1-5(1H)-one

A solution of (±)-2-amino-5-nitroindane-2-carboxamide, trifluoroacetatesalt (described in Intermediate 3, 25.0 mg, 0.075 mmol) and1,1,1-trimethoxybutane (0.060 mL, 0.373 mmol) in toluene (5 mL) washeated at reflux for 16 h. The reaction mixture was concentrated underreduced pressure to give the title compound. MS: m/z=274 (M+1).

Step B.(±)-5′-Amino-2-propyl-1′,3′-dihydrospiro[imidazole-4,2′-inden]-5(1H)-one

To a solution of(±)-5′-nitro-2-propyl-1′,3′-dihydrospiro[imidazole-4,2′-inden]-5(1H)-onefrom Step A (20.0 mg, 0.073 mmol) in degassed MeOH (5 mL) was added 10%palladium on carbon (10 mg). The suspension was placed under a hydrogenballoon for 1 h, then filtered through a pad of Celite, concentrated,and dried under high vacuum to give the title compound. MS: m/z=244(M+1).

Intermediate 5

(±)-5′-Amino-2-tert-butyl-1′,3′-dihydrospiro[imidazole-4,2′-inden]-5(1H)-oneStep A. (±)-2-[(2,2-Dimethylpropanoyl)amino]-5-nitroindane-2-carboxamide

A solution of (±)-2-amino-5-nitroindane-2-carboxamide, trifluoroacetatesalt (described in Intermediate 3, 25.0 mg, 0.075 mmol),2,2-dimethylpropanoyl chloride (0.011 mL, 0.089 mmol), and triethylamine(0.026 mL, 0.186 mmol) in THF (5 mL) was stirred at ambient temperaturefor 16 h. The reaction mixture was poured onto saturated NH₄Cl (10 mL)and extracted with CH₂Cl₂ (3×10 mL). A solid precipitate was filteredand collected, then dissolved in MeOH and combined with the organiclayers. The combined organic layers were dried over Na₂SO₄, filtered,and concentrated under reduced pressure to give the title compound. MS:m/z=306 (M+1).

Step B.(±)-2-tert-Butyl-5′-nitro-1′,3′-dihydrospiro[imidazole-4,2′-inden]-5(1H)-oneA solution of(±)-2-[(2,2-dimethylpropanoyl)amino]-5-nitroindane-2-carboxamide fromStep A (23.0 mg, 0.075 mmol) and 5N NaOH (0.075 mL, 0.38 mmol) in EtOH(5 mL) was heated to reflux for 3.5 h. The reaction mixture was pouredonto saturated NH₄Cl (10 mL) and extracted with CH₂Cl₂ (3×10 mL). Thecombined organic layers were dried over Na₂SO₄, filtered, andconcentrated under reduced pressure to give the title compound. MS:m/z=288 (M+1).

Step C,(±)-5′-Amino-2-tert-butyl-1′,3′-dihydrospiro[imidazole-4,2′-inden]-5(1H)-one

To a solution of(±)-2-tert-butyl-5′-nitro-1′,3′-dihydrospiro[imidazole-4,2′-inden]-5(1H)-onefrom Step B (22.0 mg, 0.077 mmol) in degassed MeOH (5 mL) was added 10%palladium on carbon (10 mg). The suspension was placed under a hydrogenballoon for 1 h, then filtered through a pad of Celite, concentrated,and dried under high vacuum to give the title compound. MS: m/z=258(M+1).

Intermediate 6

Essentially following the procedures outlined for Intermediate 5 thecompound listed in Table 1 was prepared. The requisite startingmaterials were commercially available, described in the literature,synthesized according to methodology described herein (vide supra), orreadily synthesized by one skilled in the art of organic synthesis.

TABLE 1 Example R^(b) MS (M + 1) 6

242

Intermediate 7

(±)-5′-Amino-2-pyrazin-2-yl-1′,3′-dihydrospiro[imidazole-4,2′-inden]-5(1H)-oneStep A.(±)-Benzyl{2-(aminocarbonyl)-2-[(pyrazin-2-ylcarbonyl)amino]-2,3-dihydro-1H-inden-5-yl}carbamate

A solution of(±)-benzyl[2-amino-2-(aminocarbonyl)-2,3-dihydro-1H-inden-5-yl]carbamate(described in Intermediate 1, 52.0 mg, 0.118 mmol),pyrazine-2-carboxylic acid (15.0 mg, 0.118 mmol), EDC (34.0 mg, 0.178mmol), HOBT (27.0 mg, 0.178 mmol), and triethylamine (0.103 mL, 0.592mmol) in DMF (5 mL) was stirred at ambient temperature for 16 h. Thereaction mixture was purified directly by HPLC using a reversed phaseC18 column and eluting with a gradient of H₂O:CH₃CN:CF₃CO₂H-90:10:0.1 to5:95:0.1. The pure, product-containing fractions were combined andconcentrated to give the title compound as the trifluoroacetate salt.MS: m/z=432 (M+1).

Step B.(±)-5′-Amino-2-pyrazin-2-yl-1′,3′-dihydrospiro[imidazole-4,2′-inden]-5(1H)-one

A solution of(±)-benzyl{2-(aminocarbonyl)-2-[(pyrazin-2-ylcarbonypamino]-2,3-dihydro-1H-inden-5-yl}carbamatefrom Step A (58.0 mg, 0.106 mmol) and 5N NaOH (0.106 mL, 0.532 mmol) inEtOH (5 mL) was heated to reflux for 5 h. The reaction mixture wasconcentrated under reduced pressure. The crude product was dissolved inDMSO (1 mL) and purified by HPLC using a reversed phase C18 column andeluting with a gradient of H₂O:CH₃CN:CF₃CO₂H-90:10:0.1 to 5:95:0.1. Thepure, product-containing fractions were combined and concentrated togive the title compound as the trifluoroacetate salt. MS: m/z=280 (M+1).

Intermediates 8-10

Essentially following the procedures outlined for Intermediate 4 thecompound listed in Table 1 was prepared. The requisite startingmaterials were commercially available, described in the literature,synthesized according to methodology described herein (vide supra), orreadily synthesized by one skilled in the art of organic synthesis.

TABLE 2 MS Example R^(b) (M + 1) 8

279 9

279 10

279

Intermediate 11

5′-Amino-2-phenyl-1′,3′-dihydrospiro[imidazole-4,2′-inden]-5(1H)-one,enantiomer A Step A.(±)-Benzyl(5-oxo-2-phenyl-1,1′,3′,5-tetrahydrospiro[imidazole-4,2′-inden]-5′-yl)carbamate

The enantiomers of(±)-5′-amino-2-phenyl-1′,3′-dihydrospiro[imidazole-4,2′-inden]-5(1H)-one(described in Intermediate 2, 35.0 mg, 0.108 mmol) were resolved using aChiralcel OJ-H column and eluting with heptanes:EtOH-40:60 with 0.1% DEAas a modifier. The first major peak to elute was the title compound,5′-amino-2-phenyl-1′,3′-dihydrospiro[imidazole-4,2′-inden]-5(1H)-one,enantiomer A. MS: m/z=278 (M+1).

Intermediate 11

5′-Amino-2-phenyl-1′,3′-dihydrospiro[imidazole-4,2′-inden]-5(1H)-one,enantiomer B Step A.(±)-Benzyl(5-oxo-2-phenyl-1,1′,3′,5-tetrahydrospiro[imidazole-4,2′-inden]-5′-yl)carbamate

The enantiomers of(±)-5′-amino-2-phenyl-1′,3′-dihydrospiro[imidazole-4,2′-inden]-5(1H)-one(described in Intermediate 2, 35.0 mg, 0.108 mmol) were resolved using aChiralcel OJ-H column and eluting with heptanes:EtOH-40:60 with 0.1% DEAas a modifier. The second major peak to elute was the title compound,5′-amino-2-phenyl-1′,3′-dihydrospiro[imidazole-4,2′-inden]-5(1H)-one,enantiomer B. MS: m/z=278 (M+1).

EXAMPLE 1

(±)-N-(5-oxo-2-phenyl-1,1′,3′,5-tetrahydrospiro[imidazole-4,2′-inden]-5′-yl)-2-[2-oxo-3-(1,3-thiazol-2-yl)-2,3-dihydro-1H-benzimidazol-1-yl]acetamide

A mixture of(±)-5′-amino-2-phenyl-1′,3′-dihydrospiro[imidazole-4,2′-inden]-5(1H)-one(10 mg, 0.036 mmol, described in Intermediate 2),[2-oxo-3-(1,3-thiazol-2-yl)-2,3-dihydro-1H-benzimidazol-1-yl]acetic acid(10 mg, 0.036 mmol) [Bell et al U.S. Pat. No. 7,202,251], EDC (10 mg,0.054 mmol), HOBT (8.0 mg, 0.054 mmol), and N,N-diisopropylethylamine(0.031 mL, 0.180 mmol) was stirred in DMF (1 mL) at ambient temperaturefor 24 h. The reaction mixture was purified directly by HPLC using areversed phase C18 column and eluting with a gradient ofH₂O:CH₃CN:CF₃CO₂H-90:10:0.1 to 5:95:0.1. The pure, product-containingfractions were combined and concentrated to give the title compound asthe trifluoroacetate salt. MS: m/z=535 (M+1). HRMS: m/z=535.1559;calculated m/z=535.1547 for C₂₉H₂₂N₆O₃S₁.

EXAMPLE 2

(±)-2-(2-oxo-3-pyridin-2-yl-2,3-dihydro-1H-benzimidazol-1-yl)-N-(5-oxo-2-pyridin-2-yl-1,1′,3′,5-tetrahydrospiro[imidazole-4,2′-inden]-5′-yl)acetamide

A mixture of(±)-5′-amino-2-pyridin-2-yl-1′,3′-dihydrospiro[imidazole-4,2′-inden]-5(1H)-one,bis-trifluoroacetate salt (26 mg, 0.051 mmol, described in Intermediate10), (2-oxo-3-pyridin-2-yl-2,3-dihydro-1H-benzimidazol-1-yl)acetic acid(15 mg, 0.056 mmol) [Bell et al. (2006) Bioorg. Med. Chem. Lett. 16,6165], EDC (15 mg, 0.077 mmol), HOBT (12 mg, 0.077 mmol), andN,N-diisopropylethylamine (0.045 mL, 0.26 mmol) was stirred in DMF (0.5mL) at ambient temperature for 72 h. The reaction mixture was purifieddirectly by HPLC using a reversed phase C18 column and eluting with agradient of H₂O:CH₃CN:CF₃CO₂H-90:10:0.1 to 5:95:0.1. The pure,product-containing fractions were combined and concentrated to give thetitle compound as the trifluoroacetate salt. MS: m/z=530 (M+1). HRMS:m/z=530.1953; calculated m/z=530.1935 for C₃₀H₂₃N₇O₃.

EXAMPLES 3-9

Essentially following the procedures outlined for Example 1 thecompounds listed in Table 3 were prepared. The requisite startingmaterials were commercially available, described in the literature,synthesized according to methodology described herein (vide supra), orreadily synthesized by one skilled in the art of organic synthesis. Insome cases, straightforward protecting group strategies were applied.

TABLE 3

Example R MS (M + 1) Intermediate 3

493 6 4

495 4 5

509 5 6

531 7 7

529 2 8

530 9 9

530 8

EXAMPLES 10-15

Essentially following the procedures outlined for Example 1 thecompounds listed in Table 4 were prepared. The requisite startingmaterials were commercially available, described in the literature,synthesized according to methodology described herein (vide supra), orreadily synthesized by one skilled in the art of organic synthesis. Insome cases, straightforward protecting group strategies were applied.

TABLE 4

Amine Exam- MS Inter- R-Literai

ple R (M + 1) mediate Referen

10

584 2 WO 2008/0

11

584 11 WO 2008/0

12

584 12 WO 2008/0

13

598 2 WO 2008/0

14

583 2 WO 2008/0

15

597 11 WO 2008/0

indicates data missing or illegible when filed

EXAMPLES 16-19

Essentially following the procedures outlined for Example 1 thecompounds listed in Table 5 are prepared. The requisite startingmaterials are commercially available, described in the literaturereferenced below, synthesized according to methodology described herein(vide supra), or readily synthesized by one skilled in the art oforganic synthesis. In some cases, straightforward protecting groupstrategies are applied.

TABLE 5

Literature Example R Reference 16

WO 2008/020902 17

WO 2008/020902 18

WO 2008/020902 19

WO 2008/020902

Although specific enantiomers and diastereomers appear in the aboveExamples and Intermediates, it is well understood by those skilled inthe art that modifications to reaction conditions and reagents (forexample, but not limited to: using the opposite chirality for startingmaterials; different catalysts; using the opposite chirality forreagents; choosing to use a different enantiomer or diasteriomersubsequent to a chiral resolution) will provide alternative enantiomersand diastereomers, all of which are included in the spirit and scope ofthe invention. It is intended that all of the possible optical isomersand diastereomers in mixtures and as pure or partially purifiedcompounds are included within the ambit of this invention. The presentinvention is meant to comprehend all such isomeric forms of thesecompounds.

The utility of the compounds in accordance with the present invention asantagonists of CORP receptor activity may be demonstrated by methodologyknown in the art. Inhibition of the binding of ¹²⁵I-CGRP to receptorsand functional antagonism of CORP receptors were determined as follows:

NATIVE RECEPTOR BINDING ASSAY: The binding of ¹²⁵I-CGRP to receptors inSK-N-MC cell membranes was carried out essentially as described(Edvinsson et al. (2001) Eur. J. Pharmacal. 415, 39-44). Briefly,membranes (25 μg) were incubated in 1 mL of binding buffer [10 mM HEPES,pH 7.4, 5 mM MgCl₂ and 0.2% bovine serum albumin (BSA)] containing 10 pM¹²⁵I-CGRP and antagonist. After incubation at room temperature for 3 h,the assay was terminated by filtration through GFB glass fibre filterplates (PerkinElmer) that had been blocked with 0.5% polyethyleneiminefor 3 h. The filters were washed three times with ice-cold assay buffer(10 mM HEPES, pH 7.4 and 5 mM MgCl₂), then the plates were air dried.Scintillation fluid (50 μL) was added and the radioactivity was countedon a Topcount (Packard Instrument). Data analysis was carried out byusing Prism and the K; was determined by using the Cheng-Prusoffequation (Cheng & Prusoff (1973) Biochem. Pharmacol, 22, 3099-3108).

RECOMBINANT RECEPTOR: Human CL receptor (Genbank accession numberL76380) was subcloned into the expression vector pIREShyg2 (BDBiosciences Clontech) as a 5′NheI and 3′ PmeI fragment. Human RAMP1(Genbank accession number AJ001014) was subcloned into the expressionvector pIRESpuro2 (BD Biosciences Clontech) as a 5′NheI and 3′NotIfragment. HEK 293 cells (human embryonic kidney cells; ATCC #CRL-1573)were cultured in DMEM with 4.5 g/L glucose, 1 mM sodium pyruvate and 2mM glutamine supplemented with 10% fetal bovine serum (FBS), 100units/mL penicillin and 100 μg/mL streptomycin, and maintained at 37° C.and 95% humidity. Cells were subcultured by treatment with 0.25% trypsinwith 0.1% EDTA in HBSS. Stable cell line generation was accomplished byco-transfecting 10 μg of DNA with 30 ug Lipofectamine 2000 (Invitrogen)in 75 cm² flasks. CL receptor and RAMP1 expression constructs wereco-transfected in equal amounts. Twenty-four hours after transfectionthe cells were diluted and selective medium (growth medium+300 μg/mLhygromycin and 1 μg/mL puromycin) was added the following day. A clonalcell line was generated by single cell deposition utilizing a FACSVantage SE (Becton Dickinson). Growth medium was adjusted to 150 μg/mLhygromycin and 0.5 μg/mL puromycin for cell propagation.

RECOMBINANT RECEPTOR BINDING ASSAY: Cells expressing recombinant humanCL receptor/RAMP1 were washed with PBS and harvested in harvest buffercontaining 50 mM HEPES, 1 mM EDTA and Complete protease inhibitors(Roche). The cell suspension was disrupted with a laboratory homogenizerand centrifuged at 48,000 g to isolate membranes. The pellets wereresuspended in harvest buffer plus 250 mM sucrose and stored at 70° C.For binding assays, 20 μg of membranes were incubated in 1 ml bindingbuffer (10 mM HEPES, pH 7.4, 5 mM MgCl₂, and 0.2% BSA) for 3 hours atroom temperature containing 10 pM ¹²⁵I-hCGRP (GE Healthcare) andantagonist. The assay was terminated by filtration through 96-well GFBglass fiber filter plates (PerkinElmer) that had been blocked with 0.05%polyethyleneimine. The filters were washed 3 times with ice-cold assaybuffer (10 mM HEPES, pH 7.4 and 5 mM MgCl₂). Scintillation fluid wasadded and the plates were counted on a Topcount (Packard). Non-specificbinding was determined and the data analysis was carried out with theapparent dissociation constant (K.) determined by using a non-linearleast squares fitting the bound CPM data to the equation below:

$Y_{obsd} = \frac{\begin{matrix}{{\left( {Y_{\max} - Y_{\min}} \right)\left( {{\% \mspace{14mu} I_{\max}} - {\%_{\mspace{14mu} {Imin}}/100}} \right)} +} \\{Y_{\min} + {\left( {Y_{\max} - Y_{\min}} \right)\left( {100 - {\% \mspace{14mu} {I_{\max}/100}}} \right)}}\end{matrix}}{1 + \left( {\lbrack{Drug}\rbrack/{K_{i}\left( {1 + {\lbrack{Radiolabel}\rbrack/K_{d}}} \right)}^{nH}} \right.}$

Where Y is observed CPM bound, Y_(max) is total bound counts, Y_(min) isnon specific bound counts, (Y_(max)-Y_(min)) is specific bound counts, %I_(max) is the maximum percent inhibition, % I min is the minimumpercent inhibition, radiolabel is the probe, and the K_(d) is theapparent dissociation constant for the radioligand for the receptor asdetermined by Hot saturation experiments.

RECOMBINANT RECEPTOR FUNCTIONAL ASSAY: Cells were plated in completegrowth medium at 85,000 cells/well in 96-well poly-D-lysine coatedplates (Corning) and cultured for ˜19 h before assay. Cells were washedwith PBS and then incubated with inhibitor for 30 min at 37° C. and 95%humidity in Cellgro Complete Serum-Free/Low-Protein medium (Mediatech,Inc.) with L-glutamine and 1 g/L BSA. Isobutyl-methylxanthine was addedto the cells at a concentration of 300 μM and incubated for 30 min at37° C. Human α-CGRP was added to the cells at a concentration of 0.3 nMand allowed to incubate at 37° C. for 5 min. After α-CGRP stimulationthe cells were washed with PBS and processed for cAMP determinationutilizing the two-stage assay procedure according to the manufacturer'srecommended protocol (cAMP SPA direct screening assay system; RPA 559;GE Healthcare). Dose response curves were plotted and IC₅₀ valuesdetermined from a 4-parameter logistic fit as defined by the equationy=((a-d)/(1+(x/c)^(b))+d, where y=response, x=dose, a=max response,d=min response, c=inflection point and b=slope.

In suitable assays, such as those described herein, the compounds of theinvention are expected to have activity as antagonists of the CGRPreceptor, generally with a K_(i) or IC₅₀ value of less than about 50 μM.Such a result is indicative of the intrinsic activity of the compoundsof the invention as antagonists of CGRP receptors.

Examplary K_(i) values in the recombinant receptor binding assay forexemplary compounds of the invention are provided in the table below:

Example Ki (nM) 1 25 2 570 3 2600 4 6400 6 630 7 35 8 130 9 160 11 0.2112 29 13 1.6

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various adaptations, changes, modifications,substitutions, deletions, or additions of procedures and protocols maybe made without departing from the spirit and scope of the invention.For example, effective dosages other than the particular dosages as setforth herein above may be applicable as a consequence of variations inthe responsiveness of the mammal being treated for any of theindications with the compounds of the invention indicated above.Likewise, the specific pharmacological responses observed may varyaccording to and depending upon the particular active compounds selectedor whether there are present pharmaceutical carriers, as well as thetype of formulation and mode of administration employed, and suchexpected variations or differences in the results are contemplated inaccordance with the objects and practices of the present invention. Itis intended, therefore, that the invention be defined by the scope ofthe claims which follow and that such claims be interpreted as broadlyas is reasonable.

1. A compound of formula I:

wherein: B is a heterocycle selected from the group consisting of:

wherein T, U, V, and W are each independently a carbon atom or anitrogen atom, wherein no more than two of T, U, V and W are nitrogenatoms; wherein X is selected from: (1) —O—, (2) —S(O)_(q)—, (3)—Si(OR^(a))—C₁₋₄alkyl-, where alkyl is unsubstituted or substituted with1-5 halo, (4) —Si(C₁₋₄alkyl)₂, where each alkyl is independentlyunsubstituted or substituted with 1-5 halo-, (5) —N(R⁸)—, (6) —(C═O)—,(7) —C(R⁸)(R^(a))—, (8) —C(N(R^(b))—SO₂R^(d))(R^(a))—, (9)—C(N(R^(b))(C═O)R^(a))(R^(a))—, (1 0) —C(N(R^(b))(C═O)OR^(a))(R^(a))—,(11) —CR¹⁰R¹¹—, (12) —N(R¹¹)—, and (13) —CR³R⁴—; B is unsubstituted orsubstituted with 1-7 substituents each independently selected from R¹,R², R³, R⁴, R¹⁰, and R¹¹, wherein R¹, R², and R³ are independentlyselected from: (1) —C₁₋₆alkyl, which is unsubstituted or substitutedwith 1-7 substituents each independently selected from: (a) halo, (b)hydroxy, (c) —O—C₁₋₆ alkyl, (d) —C₃₋₆ cycloalkyl, (e) phenyl orheterocycle, wherein heterocycle is selected from: pyridyl, pyrimidinyl,pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl,oxazolyl, thiazolyl, thienyl and morpholinyl, which phenyl orheterocycle is unsubstituted or substituted with 1-5 substituents eachindependently selected from: —C₁₋₆alkyl, —O—C₁₋₆alkyl, halo, hydroxy,trifluoromethyl and —OCF₃, (f) —CO₂R¹⁹ (g) —NR²⁰R²¹, (h) —SO₂R²², (i)—CONR^(20a)R^(21a), (j) trifluoromethyl, (k) —OCO₂R¹⁹, (l)—(NR^(20a))CO₂R¹⁹, (m) —O(CO)NR^(20a)R^(21a), (n)—(NR¹⁹)(CO)NR^(20a)R^(21a), and (o) —O—C₃₋₆cycloalkyl, (2)—C₃₋₆cycloalkyl, which is unsubstituted or substituted with 1-7substituents each independently selected from: (a) halo, (b) hydroxy,(c) —O—C₁₋₆alkyl, (d) trifluoromethyl, (e) phenyl, which isunsubstituted or substituted with 1-5 substituents each independentlyselected from: —C₁₋₆alkyl, —O—C₁₋₆alkyl, halo, hydroxy andtrifluoromethyl, (3) phenyl or heterocycle, wherein heterocycle isselected from: pyridyl, pyrimidinyl, pyrazinyl, thienyl, pyridazinyl,pyrrolidinyl, azetidinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl,imidazolyl, triazolyl, tetrazolyl, azepanyl, benzimidazolyl,benzopyranyl, benzofuryl, benzothiazolyl, benzoxazolyl, chromanyl,furyl, imidazolinyl, indolinyl, indolyl, quinolinyl, isoquinolinyl,tetrahydroquinolinyl, isoindolinyl, tetrahydroisoquinolinyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, pyrazolidinyl,pyrazolyl, pyrrolyl, quinazolinyl, tetrahydrofuryl, thiazolinyl,purinyl, naphthyridinyl, quinoxalinyl, 1,3-dioxolanyl, oxadiazolyl,piperidinyl, tetrahydropyranyl, tetrahydrothienyl,tetrahydrothiopyranyl, and morpholinyl, which phenyl or heterocycle isunsubstituted or substituted with 1-5 substituents each independentlyselected from: (a) —C₁₋₆alkyl, which is unsubstituted or substitutedwith 1-6 fluoro, (b) halo, (c) hydroxy, (d) —O—C₁₋₆alkyl, which isunsubstituted or substituted with 1-6 fluoro, (e) —C₃₋₆cycloalkyl, (f)phenyl or heterocycle, wherein heterocycle is selected from: pyridyl,pyrimidinyl, pyrazinyl, thienyl, or morpholinyl, which is unsubstitutedor substituted with 1-5 substituents where the substituents areindependently selected from: —C₁₋₆alkyl, halo, hydroxy andtrifluoromethyl, (g) —CO₂R¹⁹, (h) —(CO)R¹⁹, (i) —NR²⁰R²¹, (j)—CONR²⁰R²¹, (k) oxo, and (l) —S(O)_(q)R²², (4) halo, (5) oxo, (6)hydroxy, (7) —O—C₁₋₆alkyl which is unsubstituted or substituted with 1-5halo, (8) —CN, (9) —CO₂R¹⁹, (10) —NR²⁰R²¹, (11) —SO₂R²², (12)—CONR^(20a)R^(21a), (13) —OCO₂R¹⁹, (14) —(NR^(20a))CO₂R¹⁹, (15)—O(CO)NR^(20a)R^(21a), (16) —(NR¹⁹)(CO)NR^(20a)R^(21a), (17)—(CO)—(CO)NR^(20a)R^(21a), (18) —(CO)—(CO)OR¹⁹, (19)—SO₂NR^(20a)R^(21a), and (20) hydrogen; or R³ and R⁴ and the carbon atomto which they are attached join to form a ring selected fromcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,dioxolanyl, dioxanyl, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl,tetrahydrothiapyranyl, oxetanyl, thietanyl and tetrahydrothienyl,wherein the sulfur is optionally oxidized to the sulfone or sulfoxide,which ring is unsubstituted or substituted with 1-5 substituents eachindependently selected from: (a) —C₁₋₆allcyl, which is unsubstituted orsubstituted with 1-3 substituents each independently selected from: (i)halo, (ii) —OR^(a), (iii) —C₃₋₆cycloalkyl, (iv) —CO₂R^(a), (v)—NR^(b)R^(c), (vi) —S(O)_(q)R^(d), (vii) —C(═O)NR^(b)R^(c), and (viii)phenyl, (b) phenyl or heterocycle, wherein heterocycle is selected from:pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperdinyl, piperazinyl,pyrrolidinyl, thienyl, morpholinyl, thiazolyl and oxazolyl, wherein thephenyl or heterocycle is optionally fused to the ring, and which phenylor heterocycle is unsubstituted or substituted with 1-5 substituentseach independently selected from: (i) halo, (ii) —C₁₋₆alkyl, which isunsubstituted or substituted with 1-5 halo, (iii) —OR^(a), (iv)—CO₂R^(a), (v) —O(C═O)R^(a), (vi) —CN, (vii) —NR^(b)R^(c), (viii) oxo,(ix) —C(═O)NR^(b)R^(c), (x) —N(R^(b))C(═O)R^(a), (xi) —N(R^(b))CO₂R^(a),(xii) —O(C═O)NR^(b)R^(c), and (xiii) —S(O)_(q)R^(d), (c) —OR^(a), (d)halo, (a) —CO₂R^(a), (b) —C(═O)NR^(b)R^(c), (c) —S(O)_(q)R^(d), (d) —CN,(e) —NR^(b)R^(c), (f) —N(R^(b))C(═O)R^(a), (g) —N(R^(b))SO₂R^(d), (h)—O—CO₂R^(d), (i) —O—(C═O)—NR^(b)R^(c), (j) —NR^(b)—(C═O)—NR^(b)R^(c),(k) —C(═O)R^(a), and (l) oxo; A1 and A3 are independently selected from:(1) —O—, (2) —S(O)_(q)—, (3) —Si(OR^(a))(C₁₋₄alkyl)-, where alkyl isunsubstituted or substituted with halo, (4) —Si(C₁₋₄alkyl)₂-, where eachalkyl is independently unsubstituted or substituted with 1-5 halo-, (5)—CR^(e)R^(f)—, (6) —N(R⁴)—, (7) —(C═O)—, and (8) a bond; A² and A⁴ areindependently selected from: (1) —O—, (2) —S(O)_(q)—, (3)—Si(OR^(a))(C₁₋₄alkyl)-, where alkyl is unsubstituted or substitutedwith halo, (4) —Si(C₁₋₄alkyl)₂-, where each alkyl is independentlyunsubstituted or substituted with 1-5 halo-, (5) —CR^(e)R^(f)—, (6)—N(R⁴)—, and (7) —(C═O)—; E^(a), E^(b), and E^(c) are each independentlyselected from: (1) —C(R⁵)═, (2) —N═, and (3) —(N⁺—O)═; G¹ is selectedfrom: (1) a bond, (2) —CR^(e)R^(f)—, (3) —CR^(e)R^(f)—CH₂-, (4)—CH₂—CR^(e)R^(f)—, and (5) —(C═O)—; G² is selected from: (1) a bond, (2)—CR^(e)R^(f)—, (3) —CR^(e)R^(f)—CH₂—, (4) —CH₂—CR^(e)R^(f)—, (5)—(C═O)—, (6) —N(R⁴)—, (7) —O—, (8) —S(O)_(q)—, (9) —SiR^(g)R^(h)—, (10)—C(R^(i))═C(R^(j))—, and (11 1) —C≡C—; G³ is selected from: (1) a bond,(2) —CR^(e)R^(f)—, (3) —N(R⁴)—, (4) —O—, (5) —S(O)_(q)—, (6)—SiR^(g)R^(h)—, (7) —C(R^(i))═C(R^(j))—, (8) —C≡C—, and (9) —(C═O)—; G⁴is selected from: (1) —CR^(e)R^(f)—, (2) —N(R⁴)—, (3) —O—, (4)—S(O)_(q)—, (5) —SiR^(g)R^(h)—, (6) —C(R^(i))═C(R^(j))—, and (7) —C≡C—;R⁴ is independently selected from: (1) hydrogen, (2) —C(═O)R^(a), (3)—CO₂R^(a), (4) —S(═O)R^(d), (5) —SO₂R^(d), (6) —C(═O)NR^(b)R^(c), (7)—C₁₋₆alkyl, which is unsubstituted or substituted with 1-5 substituentseach independently selected from: (a) halo, (b) —OR^(a), (c)—C₃₋₆cycloalkyl, (d) phenyl or heterocycle, wherein said heterocycle isselected from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,piperidinyl, piperazinyl, pyrrolidinyl, thienyl, morpholinyl, thiazolyland oxazolyl, which phenyl or heterocycle is unsubstituted orsubstituted with 1-5 substituents each independently selected from: (i)halo, (ii) —C₁₋₆ alkyl, which is unsubstituted or substituted with 1-5halo, (iii) —OR^(a), (iv) —NR^(b)R^(c), (v) —C(═O)R^(a), (vi) —CO₂R^(a),and (vii) oxo; (e) —CO₂R^(a), (f) —C(═O)NR^(b)R^(c), (g) —S(O)_(q)R^(d),(h) —CN, (i) —NR^(b)R^(c), (j) —N(R^(b))C(═O)R^(a), (k)—N(R^(b))SO₂R^(d), (l) —CF₃, (m) —O—CO₂R^(d), (n) —O—(C═O)—NR^(b)R^(c),(o) —NR^(b)—(C═O)—NR^(b)R^(c), and (p) —C(═O)R^(a); (8) —C₃₋₆cycloalkyl,which is unsubstituted or substituted with 1-6 substituents eachindependently selected from: (a) halo, (b) —CN, (c) —OR^(a), and (d)C₁₋₆alkyl, which is unsubstituted or substituted with 1-6 halo; R⁵ isindependently selected from: (1) hydrogen, (2) —C₁₋₆alkyl, which isunsubstituted or substituted with 1-7 substituents each independentlyselected from: (a) halo, (b) hydroxy, (c) —OC₁₋₆alkyl, (d)—C₃₋₆cycloalkyl, (e) phenyl, (f) —CONR^(20a)R^(21a), (g) —CO₂R¹⁹, and(h) —NR²⁰R²¹, (3) —C₃₋₆cycloalkyl, which is unsubstituted or substitutedwith 1-6 fluoro, (4) phenyl or heterocycle, wherein heterocycle isselected from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperdinyl,piperazinyl, pyrrolidinyl, thienyl, morpholinyl, thiazolyl and oxazolyl,which phenyl or heterocycle is unsubstituted or substituted with 1-5substituents each independently selected from: (a) —C₁₋₄alkyl, which isunsubstituted or substituted with 1-5 fluoro, (b) halo, (c) —CN, (d)hydroxy, and (e) —O—C₁₋₆ alkyl, which is unsubstituted or substitutedwith 1-6 fluoro, (5) halo, (6) hydroxy, (7) —OC₁₋₆alkyl, which isunsubstituted or substituted with 1-5 halo, (8) —CN, (9) —CO₂R¹⁹, (10)—NR₂₀R²¹, (11) —SO₂R²², (12) —CONR^(20a)R^(21a), (13) —OCO₂R¹⁹, and (14)—(NR^(20a))CO₂R¹⁹; R⁶ is selected from: (1) hydrogen; (2) —C₁₋₆alkyl,which is unsubstituted or substituted with 1-6 substituents eachindependently selected from: (a) halo, (b) —O—C₁₋₆alkyl, which isunsubstituted or substituted with 1-6 fluoro, (c) —C₃₋₆cycloalkyl, whichis unsubstituted or substituted with 1-6 fluoro, and (d) phenyl orheterocycle, wherein heterocycle is selected from: azepinyl, azepanyl,azetidinyl, benzimidazolyl, benzisoxazolyl, benzofuranyl,benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl,benzothiazolyl, benzothienyl, benzoxazolyl, benzopyrazolyl,benzotriazolyl, dibenzofuranyl, dihydrobenzofuryl, dihydrobenzothienyl,dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl,furanyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl,isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl,morpholinyl, naphthyridinyl, oxazolyl, oxadiazolyl, 2-oxoazepinyl,4-oxonaphthyridinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolidinyl, 2-oxopyridyl, 2-oxoquinolinyl, piperidyl,piperazinyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl,pyridinyl, pyridyl, pyrimidinyl, pyrimidyl, pyrrolidinyl, pyrrolyl,quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuranyl,tetrahydrofuryl, tetrahydroimidazopyridinyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, tetrazolyl, thiamorpholinyl, thiamorpholinylsulfoxide, thiamorpholinyl sulfone, thiazolyl, thiazolinyl, thienofuryl,thienothienyl, thienyl, isoxazolyl, tetrahydrothienyl,tetrahydropyranyl, oxetanyl, tetrahydrothiapyranyl, thietanyl, andtriazolyl, which phenyl or heterocycle is unsubstituted or substitutedwith 1-3 substituents each independently selected from: —C₁₋₆alkyl,—O—C₁₋₆alkyl, halo, hydroxy, trifluoromethyl, —CN, and —OCF₃, (3) phenylor heterocycle, wherein heterocycle is selected from: azepinyl,azepanyl, azetidinyl, benzimidazolyl, benzisoxazolyl, benzofuranyl,benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl,benzothiazolyl, benzothienyl, benzoxazolyl, benzopyrazolyl,benzotriazolyl, dibenzofuranyl, dihydrobenzofuryl, dihydrobenzothienyl,dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl,furanyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl,isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl,morpholinyl, naphthyridinyl, oxazolyl, oxadiazolyl, 2-oxoazepinyl,4-oxonaphthyridinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolidinyl, 2-oxopyridyl, 2-oxoquinolinyl, piperidyl,piperazinyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl,pyridinyl, pyridyl, pyrimidinyl, pyrimidyl, pyrrolidinyl, pyrrolyl,quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuranyl,tetrahydrofuryl, tetrahydroimidazopyridinyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, tetrazolyl, thiamorpholinyl, thiamorpholinylsulfoxide, thiamorpholinyl sulfone, thiazolyl, thiazolinyl, thienofuryl,thienothienyl, thienyl, isoxazolyl, tetrahydrothienyl,tetrahydropyranyl, oxetanyl, tetrahydrothiapyranyl, thietanyl, andtriazolyl, which phenyl or heterocycle is unsubstituted or substitutedwith 1-3 substituents each independently selected from: (a) halo, (b)—OR^(a), (c) —C₃₋₆cycloalkyl, which is unsubstituted or substituted with1-6 fluoro, (d) phenyl, which is unsubstituted or substituted with 1-5substituents each independently selected from: (i) halo, (ii) —CN, (iii)—C₁₋₆alkyl, which is unsubstituted or substituted with 1-6 halo, and(iv) —OR^(a), (a) —CO₂R^(a), (f) —C(═O)NR^(b)R^(c), (a) —S(O)_(q)R^(d),(b) —CN, (c) —NR^(b)R^(c), (j) —N(R^(b))C(═O)R^(a), (k)—N(R^(b))SO₂R^(d), (l) —O—CO₂R^(d), (m) —O—(C═O)—NR^(b)R^(c), (n)—NR^(b)—(C═O)—NR^(b)R^(c), (o) —C(═O)R^(a), and (p) —C₁₋₆alkyl, which isunsubstituted or substituted with 1-6 halo, (4) —O—C₁₋₆alkyl, which isunsubstituted or substituted with 1-5 halo, (5) —CN, (6) —CO₂R¹⁹, (7)—NR²⁰R²¹, and (8) —CONR^(20a)R^(21a) (9) —C₁₋₆cycloalkyl, which isunsubstituted or substituted with 1-5 substituents each independentlyselected from: (a) halo, (b) —CN, (c) —C₁₋₆alkyl, which is unsubstitutedor substituted with 1-5 halo, (d) —OR^(a), and (e) phenyl, which isunsubstituted or substituted with 1-5 substituents where thesubstituents are each independently selected from: (i) —OR^(a), (ii)halo, (iii) —CN, and (iv) —C₁₋₆allcyl, which is unsubstituted orsubstituted with 1-5 halo, R⁸ is independently selected from: (1)hydrogen, (2) —C(═O)R^(a), (3) —CO₂R^(a), (4) —S(═O)R^(d), (5)—SO₂R^(d), (6) —C(═O)NR^(b)R^(c), (7) —C₁₋₆allcyl, which isunsubstituted or substituted with 1-5 substituents each independentlyselected from: (a) halo, (b) —OR^(a), (c) —C₃₋₆cycloalkyl, (d) phenyl orheterocycle, wherein said heterocycle is selected from: pyridyl,pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl,pyrrolidinyl, thienyl, morpholinyl, thiazolyl and oxazolyl, which phenylor heterocycle is unsubstituted or substituted with 1-5 substituentseach independently selected from: (i) halo, (ii) —C₁₋₆allcyl, which isunsubstituted or substituted with 1-5 halo, (iii) —OR^(a), (iv)—NR^(b)R^(c), (v) —C(═O)R^(a), (vi) —CO₂R^(a), (vii) oxo, and (viii)—CN, (e) —CO₂R^(a), (f) —C(═O)NR^(b)R^(c), (g) —S(O)_(q)R^(d), (h) —CN,(i) —NR^(b)R^(c), (j) —N(R^(b))C(═O)R^(a), (k) —N(R^(b))SO₂R^(d), (l)—CF₃, (m) —O—CO₂R^(d), (n) —O—(C═O)—NR^(b)R^(c), (o)—NR^(b)—(C═O)—NR^(b)R^(c), and (p) —C(═O)R^(a), (8) —C₃₋₆cycloalkyl,which is unsubstituted or substituted with 1-6 substituents eachindependently selected from: (a) halo, (b) —CN, (c) —OR^(a), and (d)C₁₋₆alkyl, which is unsubstituted or substituted with 1-6 halo; or R⁴and R⁸ and the atoms to which they are attached join to form a 4-, 5-,6- or 7-membered alkyl- or heteroalkyl-ring optionally containing anadditional heteroatom selected from N, O, and S, wherein the sulfur isoptionally oxidized to the sulfone or sulfoxide, which ring isunsubstituted or substituted with 1-4 substituents each independentlyselected from: (a) halo, (b) phenyl, which is unsubstituted orsubstituted with 1-3 substituents each independently selected from:halo, OR^(a), CN, and —C(═O)OR^(a), (c) —OR^(a), and (d) —C₁₋₆alkyl,which is unsubstituted or substituted with 1-6 halo; R¹⁰ isindependently selected from: (1) hydrogen, (2) —C₁₋₆alkyl, which isunsubstituted or substituted with 1-5 substituents each independentlyselected from: (a) halo, (b) —OR^(a), (c) —CN, (d) phenyl, and (e)—C₃₋₆cycloalkyl, which is unsubstituted or substituted with 1-6 halo,(3) —C₃₋₆cycloalkyl, which is unsubstituted or substituted with 1-6halo; R¹¹ is independently selected from the group consisting of:phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl,anthryl, azepinyl, azepanyl, azetidinyl, benzimidazolyl, benzisoxazolyl,benzofuranyl, benzofurazanyl, benzopyranyl, benzothiopyranyl,benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, benzopyrazolyl,benzotriazolyl, chromanyl, cinnolinyl, dibenzofuranyl,dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl,dihydrobenzothiopyranyl sulfone, furyl, furanyl, imidazolidinyl,imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl,isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl,morpholinyl, naphthyridinyl, oxazolyl, oxadiazolyl, 2-oxoazepinyl,4-oxonaphthyridinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolidinyl, 2-oxopyridyl, 2-oxoquinolinyl, piperidyl,piperazinyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl,pyridinyl, pyridyl, pyrimidinyl, pyrimidyl, pyrrolidinyl, pyrrolyl,quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuranyl,tetrahydrofuryl, tetrahydroimidazopyridinyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, tetrazolyl, thiamorpholinyl, thiamorpholinylsulfoxide, thiamorpholinyl sulfone, thiazolyl, thiazolinyl, thienofuryl,thienothienyl, thienyl, triazolyl, isoxazolyl, tetrahydrothienyl,tetrahydropyranyl, oxetanyl, tetrahydrothiapyranyl, and thietanyl, whereR¹¹ is unsubstituted or substituted with 1-5 substituents eachindependently selected from R¹², R¹³, R¹⁴, R^(15a) and R^(15b); R¹²,R¹³, R¹⁴, R^(15a) and R^(15b) are each independently selected from: (1)—C₁₋₆allcyl, which is unsubstituted or substituted with 1-5 substituentseach independently selected from: (a) halo, (b) —OR^(a), (c)—C₃₋₆cycloalkyl, (d) phenyl or heterocycle, wherein said heterocycle isselected from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperdinyl,piperazinyl, pyrrolidinyl, thienyl, morpholinyl, thiazolyl and oxazolyl,which phenyl or heterocycle is unsubstituted or substituted with 1-5substituents each independently selected from: (i) halo, (ii)—C₁₋₆alkyl, which is unsubstituted or substituted with 1-5 halo, and(iii) —OR^(a), (e) —CO₂R^(a), (f) —C(═O)NR^(b)R^(c), (g) —S(O)_(q)R^(d),(h) —CN, (i) —NR^(b)R^(c), (j) —N(R^(b))C(═O)R^(a), (k)—N(R^(b))SO₂R^(d), (l) —CF₃, (m) —O—CO₂R^(d), (n) —O—(C═O)—NR^(b)R^(c),(o) —NR^(b)—(C═O)—NR^(b)R^(c), and (p) —C(═O)R^(a), (2) —C₁₋₆cycloalkyl,which is unsubstituted or substituted with 1-5 substituents eachindependently selected from: (a) halo, (b) —CN, (c) —C₁₋₆alkyl, which isunsubstituted or substituted with 1-5 halo, (d) —OR^(a), and (e) phenyl,which is unsubstituted or substituted with 1-5 substituents where thesubstituents are each independently selected from: (i) —OR^(a), (ii)halo, (iii) —CN, and (iv) —C₁₋₆alkyl, which is unsubstituted orsubstituted with 1-5 halo, (3) phenyl or heterocycle, wherein saidheterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl,pyridazinyl, piperdinyl, piperazinyl, pyrrolidinyl, thienyl,morpholinyl, thiazolyl and oxazolyl, which phenyl or heterocycle isunsubstituted or substituted with 1-5 substituents each independentlyselected from: (a) halo, (b) —OR^(a), (c) —C₃₋₆cycloalkyl, which isunsubstituted or substituted with 1-6 halo, (d) phenyl, which isunsubstituted or substituted with 1-5 substituents each independentlyselected from: (i) halo, (ii) —C₁₋₆alkyl, which is unsubstituted orsubstituted with 1-6 halo, and (iii) —OR^(a), (e) —CO₂R^(a), (f)—C(═O)NR^(b)R^(c), (g) —S(O)_(q)R^(d), (h) —CN, (i) —NR^(b)R^(c), (j)—N(R^(b))C(═O)R^(a), (k) —N(R^(b))SO₂R^(d), (l) —O—CO₂R^(d), (m)—O—(C═O)—NR^(b)R^(c), (n) —NR^(b)—(C═O)—NR^(b)R^(c), (o) —C(═O)R^(a),and (p) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-6 halo,(4) halo, (5) oxo, (6) —OR^(a), (7) —CN, (8) —CO₂R^(a), (9) —C(═O)R^(a),(10) —NR^(b)R^(c), (11) —S(O),_(:i)R^(d), (12) —C(═O)NR^(b)R^(c), (13)—O—CO₂R^(d), (14) —N(R^(b))CO₂R^(d), (15) —O—(C═O)—NR^(b)R^(c), (16)—NR^(b)—(C═O)—NR^(b)R^(c), (17) —SO₂NR^(b)R^(c), (18) —N(R^(b))SO₂R^(d),or R^(15a) and R^(15b) and the atom(s) to which they are attached jointo form a ring selected from cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, aziridinyl, azetidinyl, pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl, thietanyl and tetrahydrothienyl,wherein the sulfur is optionally oxidized to the sulfone or sulfoxide,which ring is unsubstituted or substituted with 1-5 substituents eachindependently selected from: (a) —C₁₋₆allcyl, which is unsubstituted orsubstituted with 1-3 substituents each independently selected from: (i)halo, (ii) —OR^(a), (iii) —C₃₋₆cycloalkyl, which is unsubstituted orsubstituted with 1-6 halo, (iv) —CO₂R^(a), (v) —NR^(b)R^(c), (vi)—S(O)_(q)R^(d), (vii) —C(═O)NR^(b)R^(c), and (viii) phenyl, (b) phenylor heterocycle, wherein said heterocycle is selected from: pyridyl,pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl,pyrrolidinyl, thienyl, morpholinyl, thiazolyl and oxazolyl, which phenylor heterocycle is unsubstituted or substituted with 1-5 substituentseach independently selected from: (i) halo, (ii) —C₁₋₆allcyl, which isunsubstituted or substituted with 1-5 halo, and (iii) —OR^(a), (c)—OR^(a), (d) halo, (e) —CO₂R^(a), (f) —C(═O)NR^(b)R^(c), (g)—S(O)_(q)R^(d), (h) —CN, (i) —NR^(b)R^(c), (j) —N(R^(b))C(═O)R^(a), (k)—N(R^(b))SO₂R^(d), (l) —O—CO₂R^(d), (m) —O—(C═O)—NR^(b)R^(c), (n)—NR^(b)—(C═O)—NR^(b)R^(c), and (o) —C(═O)R^(a); R¹⁹ is independentlyselected from: (1) hydrogen, (2) —C₁₋₆alkyl, which is unsubstituted orsubstituted with 1-6 substituents, each independently selected from: (a)halo, (b) hydroxy, (c) —OC₁₋₆alkyl, which is unsubstituted orsubstituted with 1-5 halo, (d) —C₃₋₆cycloalkyl, which is unsubstitutedor substituted with 1-6 halo, and (e) phenyl, which is unsubstituted orsubstituted with 1-5 substituents each independently selected from: (i)(ii) —OC₁₋₆alkyl, (iii) halo, (iv) trifluoromethyl, and (v) —OCF₃, (3)—C₃₋₆cycloalkyl, which is unsubstituted or substituted with 1-6substituents, substituents each independently selected from: (a) halo,(b) hydroxy, (c) —O—C₁₋₆alkyl, which is unsubstituted or substitutedwith 1-5 halo, (d) —C₁₋₆alkyl, which is unsubstituted or substitutedwith 1-5 halo, and (e) phenyl, (4) phenyl or heterocycle, whereinheterocycle is selected from: pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, thienyl, pyrrolidinyl, thiazolyl, oxazolyl, imidazolyl,triazolyl, tetrazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl,imidazolinyl, indolinyl, indolyl, quinolinyl, isoquinolinyl,tetrahydroquinolinyl, isoindolinyl, tetrahydroisoquinolinyl,tetrahydrofuryl, quinoxalinyl, piperidinyl, piperazinyl, andmorpholinyl, which phenyl or heterocycle is unsubstituted or substitutedwith 1-5 substituents each independently selected from: (a) halo, (b)—C₁₋₆alkyl, which is unsubstituted or substituted with 1-5 halo (c)—OC₁₋₆alkyl, which is unsubstituted or substituted with 1-5 halo (d)—C₃₋₆cycloalkyl, (e) oxo, (f) —CN, (g) hydroxy, and (h) phenyl; R²⁰ andR²¹ are each independently selected from: (1) hydrogen, (2) —C₁₋₆alkyl,which is unsubstituted or substituted with 1-6 substituents eachindependently selected from: (a) halo, (b) hydroxy, (c) —OCF₃, (d)—C₃₋₆cycloalkyl, which is unsubstituted or substituted with 1-6 halo,and (e) phenyl, which is unsubstituted or substituted with 1-5substituents each independently selected from: (i) —C₁₋₆alkyl, which isunsubstituted or substituted with 1-5 halo, (ii) —OC₁₋ ₆alkyl, which isunsubstituted or substituted with 1-5 halo, (iii) —CN (iv) halo, and (v)trifluoromethyl, (3) —C₃₋₆cycloalkyl, which is unsubstituted orsubstituted with 1-6 halo, (4) phenyl, which is unsubstituted orsubstituted with 1-5 substituents each independently selected from: (a)—C₁₋₆alkyl, which is unsubstituted or substituted with 1-5 halo, (b)—OC₁₋₆alkyl, which is unsubstituted or substituted with 1-5 halo, (c)halo, (d) hydroxy, (e) trifluoromethyl, (f) —OCF₃, and (g) —CN, (5)—COR¹⁹, and (6) —SO₂R²²; R^(20a) and R^(21a) are each independentlyselected from: (1) hydrogen, (2) —C₁₋₆alkyl, which is unsubstituted orsubstituted with 1-6 substituents each independently selected from: (a)—O—C₁₋₆alkyl, which is unsubstituted or substituted with 1-5 halo, (b)halo, (c) hydroxy, (d) —OCF₃, (e) —C₃₋₆cycloalkyl, and (f) phenyl, whichis unsubstituted or substituted with 1-5 substituents each independentlyselected from: (i) —C₁₋₆alkyl, which is unsubstituted or substitutedwith 1-5 halo, (ii) —OC₁₋₆alkyl, which is unsubstituted or substitutedwith 1-5 halo, (iii) —CN (iv) halo, and (v) trifluoromethyl, (3)—C₃₋₆cycloalkyl, which is unsubstituted or substituted with 1-5 halo,(4) phenyl, which is unsubstituted or substituted with 1-5 substituentseach independently selected from: (a) —C₁₋₆alkyl, which is unsubstitutedor substituted with 1-5 halo, (b) —OC₁₋₆alkyl, which is unsubstituted orsubstituted with 1-5 halo, (c) halo, (d) hydroxy, (e) trifluoromethyl,(f) —OCF₃, and (g) —CN, or where R^(20a) and R^(21a) join to form a ringselected from azetidinyl, pyrrolidinyl, piperidinyl, azepanyl,piperazinyl and morpholinyl, which ring is unsubstituted or substitutedwith 1-5 substituents each independently selected from: (1) —C₁₋₆alkyl,which is unsubstituted or substituted with 1-5 halo, (2) —O—C₁₋₆alkyl,which is unsubstituted or substituted with 1-5 halo, (3) halo (4)hydroxy (5) phenyl, which is unsubstituted or substituted with 1-5substituents each independently selected from: (a) —C₁₋₄alkyl, which isunsubstituted or substituted with 1-3 halo, (b) —O—C₁₋₄alkyl, which isunsubstituted or substituted with 1-3 halo, and (c) halo, (6) benzyl,which is unsubstituted or substituted with 1-5 substituents eachindependently selected from: (a) —C₁₋₄alkyl, which is unsubstituted orsubstituted with 1-3 halo, (b) —OC₁₋₄alkyl, which is unsubstituted orsubstituted with 1-3 halo, and (c) halo, (7) —COR¹⁹, and (8) —SO₂R²²;R²² is selected from: (1) —C₁₋₆alkyl, which is unsubstituted orsubstituted with 1-6 fluoro, (2) —C₃₋₆cycloalkyl, which is unsubstitutedor substituted with 1-5 halo, (3) phenyl or heterocycle, whereinheterocycle is selected from: pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl andmorpholinyl, which phenyl or heterocycle is unsubstituted or substitutedwith 1-5 substituents each independently selected from: (a) —C₁₋₆alkyl,which is unsubstituted or substituted with 1-5 halo, (b) —O—C₁₋₆alkyl,which is unsubstituted or substituted with 1-5 halo, (c) halo, (d)hydroxy, (e) trifluoromethyl, (f) —OCF₃, (g) —CN, and (h) benzyl, whichis unsubstituted or substituted with 1-5 substituents each independentlyselected from: (i) —C₁₋₆alkyl, which is unsubstituted or substitutedwith 1-5 halo, (ii) —O—C₁₋₆alkyl, which is unsubstituted or substitutedwith 1-5 halo, (iii) halo, and (iv) trifluoromethyl; R^(PG) is selectedfrom: (1) hydrogen, (2) —C₁₋₆alkyl, which is unsubstituted orsubstituted with 1-6 substituents each independently selected from: (a)—O—C₁₋₆alkyl, which is unsubstituted or substituted with 1-5 halo, (b)halo, (c) hydroxy, (d) —OCF₃, (e) —C₃₋₆cycloalkyl, and (f) phenyl, whichis unsubstituted or substituted with 1-5 substituents each independentlyselected from: (i) —C₁₋₆allcyl, which is unsubstituted or substitutedwith 1-6 halo, (ii) —OR^(a), (iii) —CN (iii) halo, and (iv)trifluoromethyl, (3) —CH₂OR^(a), (4) —CH₂—O—CH₂CH₂Si(CH₃)₃, R^(a) isindependently selected from: (1) hydrogen, (2) C₁₋₆allcyl, which isunsubstituted or substituted with 1-7 substituents each independentlyselected from: (a) halo, (b) —O—C₁₋₆alkyl, which is unsubstituted orsubstituted with 1-6 halo, (c) hydroxyl, (d) —C₃₋₆cycloalkyl, which isunsubstituted or substituted with 1-6 halo, (e) —CN, and (f) phenyl orheterocycle wherein said heterocycle is selected from pyridyl,pyrimidinyl, thienyl, pyridazinyl, piperidinyl, azetidinyl, furanyl,piperazinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl,tetrahydropyranyl and pyrazinyl, which phenyl or heterocycle isunsubstituted or substituted with 1-3 substituents each independentlyselected from: (i) halo, (ii) —O—C₁₋₆alkyl, which is unsubstituted orsubstituted with 1-6 halo, (iii) —CN, (iv) nitro, (v) hydroxyl, and (vi)—C₁₋₆allcyl, which is unsubstituted or substituted with 1-6 halo, (3)phenyl or heterocycle wherein said heterocycle is selected from pyridyl,pyrimidinyl, thienyl, pyridazinyl, piperidinyl, azetidinyl, furanyl,piperazinyl, pyrrolidinyl morpholinyl, tetrahydrofuranyl,tetrahydropyranyl and pyrazinyl, which phenyl or heterocycle isunsubstituted or substituted with 1-3 substituents each independentlyselected from: (a) halo, (b) —CN, (c) —O—C₁₋₆alkyl, which isunsubstituted or substituted with 1-6 halo, (d) nitro, (e) hydroxyl, and(f) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-6 halo, and(4) —C₃₋₆cycloalkyl, which is unsubstituted or substituted with 1-6halo; R^(b) and R^(c) are independently selected from: (1) hydrogen, (2)C₁₋₆allcyl, which is unsubstituted or substituted with 1-7 substituentseach independently selected from: (a) halo, (b) —OR^(a), (c) —CN, (d)—CO₂R^(a), (e) phenyl or heterocycle, wherein said heterocycle isselected from pyridyl, pyrimidinyl, thienyl, pyridazinyl, piperidinyl,azetidinyl, furanyl, piperazinyl, pyrrolidinyl, morpholinyl,tetrahydrofuranyl, tetrahydropyranyl and pyrazinyl, which phenyl orheterocycle is unsubstituted or substituted with 1-3 substituents eachindependently selected from: (i) halo, (ii) —OR^(a), (iii) —C₁₋₆alkyl,which is unsubstituted or substituted with 1-6 halo, and (iv) nitro, (3)phenyl or heterocycle, wherein said heterocycle is selected frompyridyl, pyrimidinyl, thienyl, pyridazinyl, piperidinyl, azetidinyl,furanyl, piperazinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl,tetrahydropyranyl and pyrazinyl, which phenyl or heterocycle isunsubstituted or substituted with 1-3 substituents each independentlyselected from: (a) halo, (b)—OR^(a), (c)—C₁₋₆alkyl, which isunsubstituted or substituted with 1-6 halo, (d)—C₃₋₆cycloalkyl, which isunsubstituted or substituted with 1-6 halo, (e)—CN, and (f)—CO₂R^(a),(4) —C₃₋₆cycloalkyl, which is unsubstituted or substituted with 1-6halo; or R^(b) and R^(c) and the nitrogen to which they are attachedjoin to form a 4-, 5-, or 6-membered ring optionally containing anadditional heteroatom selected from N, O, and S, wherein the sulfur isoptionally oxidized to the sulfone or sulfoxide, which ring isunsubstituted or substituted with 1-4 substituents each independentlyselected from: (i) halo, (ii) —OR^(a), and (iii) —C₁₋₆allcyl, which isunsubstituted or substituted with 1-6 halo, and (iv) phenyl; R^(d) isindependently selected from: (1) C₁₋₆allcyl, which is unsubstituted orsubstituted with 1-4 substituents each independently selected from: (a)halo, (b) —OR^(a), (c) —CO₂R^(a), (d) —CN, and (e) phenyl orheterocycle, wherein said heterocycle is selected from pyridyl,pyrimidinyl, thienyl, pyridazinyl, piperidinyl, azetidinyl, furanyl,piperazinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl,tetrahydropyranyl and pyrazinyl, which phenyl or heterocycle isunsubstituted or substituted with 1-3 substituents each independentlyselected from: (i) halo, (ii) —OR^(a), (iii) —C₁₋₆allcyl, which isunsubstituted or substituted with 1-6 halo, and (iv) nitro, (2) phenylor heterocycle, wherein said heterocycle is selected from pyridyl,pyrimidinyl, thienyl, pyridazinyl, piperidinyl, azetidinyl, furanyl,piperazinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl,tetrahydropyranyl and pyrazinyl, which phenyl or heterocycle isunsubstituted or substituted with 1-3 substituents each independentlyselected from: (a) halo, (b)—OR^(a), (c)—C₁₋₆alkyl, which isunsubstituted or substituted with 1-6 halo, (d)—C₃₋₆cycloalkyl, which isunsubstituted or substituted with 1-6 halo (e) —CN, and (f) —CO₂R^(a),and (3) —C₃₋₆cycloalkyl, which is unsubstituted or substituted with 1-6halo; R^(e) and R^(f) are independently selected from: (1) hydrogen, (2)—C₁₋₄alkyl, which is unsubstituted or substituted with 1-6 halo, (3)—OR^(a), (4) —CN, (5) halo, (6) phenyl, and (7) benzyl; and R^(e) andR^(f) and the carbon atom or atoms to which they are attached may jointo form a 3-, 4-, 5-, or 6-membered ring optionally containing aheteroatom selected from N, O, and S, wherein the sulfur is optionallyoxidized to the sulfone or sulfoxide, which ring is unsubstituted orsubstituted with 1-4 substituents each independently selected from: (a)halo, (b) —OR^(a), (c) —C₁₋₆alkyl, which is unsubstituted or substitutedwith 1-6 halo, and (d) phenyl; R^(g) and R^(h) are independentlyselected from: (1) —C₁₋₄alkyl, which is unsubstituted or substitutedwith 1-6 halo, (2) —OR^(a), (3) —C₃₋₆cycloalkyl, which is unsubstitutedor substituted with 1-6 halo, (4) phenyl, and (5) benzyl; and R^(g) andR^(h) and the silicon atom to which they are attached may join to form a3-, 4-, 5-, or 6-membered ring optionally containing a heteroatomselected from N, O, and S, wherein the sulfur is optionally oxidized tothe sulfone or sulfoxide, which ring is unsubstituted or substitutedwith 1-4 substituents each independently selected from: (a) halo, (b)—OR^(a), (c) —C₁₋₄alkyl, which is unsubstituted or substituted with 1-3halo, and (d) phenyl; R^(i) and R^(j) are independently selected from:(1) hydrogen, (2) —C₁₋₄alkyl, which is unsubstituted or substituted with1-6 halo, (3) —OR^(a), (4) halo, (5) phenyl, and (6) benzyl; q is 0, 1,or 2; or a pharmaceutically acceptable salt thereof and individualenantiomers and diastereomers thereof.
 2. A compound of claim 1 whereinB is selected from the group consisting of:

which is unsubstituted or substituted with 1-7 substituents eachindependently selected from R¹, R², R³, R⁴, R¹⁰, and R¹¹, wherein T, U,V, W, X, R¹, R², R³, R⁴, R¹⁰, and R¹¹ are defined herein; andpharmaceutically acceptable salts thereof and individual enantiomers anddiastereomers thereof.
 3. A compound of claim 2, wherein B is selectedfrom the group consisting of:

which is unsubstituted or substituted with 1-7 substituents eachindependently selected from R¹, R², R³, R⁴, R¹⁰, and R¹¹, wherein R¹,R², R³, R⁴, R¹⁰, and R¹¹ are defined and pharmaceutically acceptablesalts thereof and individual enantiomers and diastereomers thereof.
 4. Acompound of any of claim 1, or a pharmaceutically acceptable saltthereof, wherein R¹, R², and R³ are each independently selected from:(1) —C₁₋₆alkyl, which is unsubstituted or substituted with 1-7substituents each independently selected from: (a) fluoro, (b) hydroxy,(c) —O—C₁₋₆ alkyl, (d) —C₃₋₆ cycloalkyl, (e) phenyl or heterocycle,wherein heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl,pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, oxazolyl,thiazolyl, thienyl and morpholinyl, which phenyl or heterocycle isunsubstituted or substituted with 1-5 substituents each independentlyselected from: —C₁₋₆alkyl, —O—C₁₋₆alkyl, halo, hydroxy, trifluoromethyland —OCF₃, (f) —CO₂R¹⁹ (g) —NR²⁰R²¹, (h) —SO₂R²², (i)—CONR^(20a)R^(21a), (j) trifluoromethyl, (k) —(NR^(20a))CO₂R¹⁹, (l)—(NR¹⁹)(CO)NR^(20a)R^(21a), and (m) —O—C₃₋₆cycloalkyl, (2)—C₃₋₆cycloalkyl, which is unsubstituted or substituted with 1-7substituents each independently selected from: (a) fluoro, (b) hydroxy,(c) —O—C₁₋₆alkyl, (d) trifluoromethyl, and (e) phenyl, which isunsubstituted or substituted with 1-5 substituents each independentlyselected from: —C₁₋₆alkyl, —O—C₁₋₆alkyl, halo, hydroxy andtrifluoromethyl, (3) phenyl or heterocycle, wherein heterocycle isselected from: pyridyl, pyrimidinyl, pyrazinyl, thienyl, pyridazinyl,pyrrolidinyl, azetidinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl,imidazolyl, triazolyl, tetrazolyl, azepanyl, benzimidazolyl,benzopyranyl, benzofuryl, benzothiazolyl, benzoxazolyl, chromanyl,furyl, imidazolinyl, indolinyl, indolyl, quinolinyl, isoquinolinyl,tetrahydroquinolinyl, isoindolinyl, tetrahydroisoquinolinyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, pyrazolidinyl,pyrazolyl, pyrrolyl, quinazolinyl, tetrahydrofuryl, thiazolinyl,purinyl, naphthyridinyl, quinoxalinyl, 1,3-dioxolanyl, oxadiazolyl,piperidinyl, tetrahydropyranyl, tetrahydrothienyl,tetrahydrothiopyranyl, and morpholinyl, which phenyl or heterocycle isunsubstituted or substituted with 1-5 substituents each independentlyselected from: (a) —CF₃, (b) halo, (c) hydroxy, (d) —O—CF₃, (e)—C₃₋₆cycloalkyl, (f) —CO₂R¹⁹, (g) —(CO)R¹⁹, (h) —CONR²⁰R²¹, (i) oxo, and(j) —S(O)_(q)R²², (4) halo, (5) oxo, (6) hydroxy, (7) —O—C₁₋₆alkyl whichis unsubstituted or substituted with 1-5 halo, (8) —CN, (9) —CO₂R¹⁹,(10) —NR²⁰R²¹, (11) —SO₂R²², (12) —CONR^(20a)R^(21a), (13)—SO₂NR^(20a)R^(21a), and (14) hydrogen.
 5. A compound of any of claim 1,or a pharmaceutically acceptable salt thereof, wherein R³ and R⁴ and thecarbon atom to which they are attached join to form a ring selected fromcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,dioxolanyl, dioxanyl, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl,tetrahydrothiapyranyl, oxetanyl, thietanyl and tetrahydrothienyl,wherein the sulfur is optionally oxidized to the sulfone or sulfoxide,which ring is unsubstituted or substituted with 1-5 substituents eachindependently selected from: (a) —C₁₋₆allcyl, which is unsubstituted orsubstituted with 1-3 substituents each independently selected from: (i)halo, (ii) —OR^(a), (iii) —C₃₋₆cycloalkyl, (iv) —CO₂R^(a), (v)—NR^(b)R^(c), (vi) —S(O)_(q)R^(d), (vii) —C(═O)NR^(b)R^(c), and (viii)phenyl, (b) phenyl or heterocycle, wherein heterocycle is selected from:pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperdinyl, piperazinyl,pyrrolidinyl, thienyl, morpholinyl, thiazolyl and oxazolyl, wherein thephenyl or heterocycle is optionally fused to the ring, and which phenylor heterocycle is unsubstituted or substituted with 1-5 substituentseach independently selected from: (i) halo, (ii) —CF₃ (iii) —OR^(a),(iv) —CO₂R^(a), (v) —O(C═O)R^(a), (vi) —CN, (vii) oxo, and (viii)—C(═O)NR^(b)R^(c), (c) halo, (d) —CO₂R^(a), (e) —C(═O)NR^(b)R^(c), (f)—CN, (g) —C(═O)R^(a), and (h) oxo.
 6. A compound of any of claim 1, or apharmaceutically acceptable salt thereof, wherein X is selected from:(1) —O—, (2) —S(O)_(q)—, (3) —N(R⁸)—, (4) —(C═O)—, (5) —C(R⁸)(R^(a))—,(6) —C(N(R^(b))—SO₂R^(d))(R^(a))—, (7) —C(N(R^(b))(C═O)R^(a))(R^(a))—,(8) —C(N(R^(b))(C═O)OR^(a))(R^(a))—, (9) —CR¹⁰R¹¹—, (10) —N(R¹¹)—, and(11) —CR³R⁴—.
 7. A compound of any of claims claim 1 te-6, or apharmaceutically acceptable salt thereof, wherein A¹ and A³ areindependently selected from: (1) —O—, (2) —CR^(e)R^(f)—, (3) —N(R⁷)—,(4) —(C═O)—, and (5) a bond.
 8. A compound of any claim 1, or apharmaceutically acceptable salt thereof, wherein A² and A⁴ areindependently selected from: (1) —O—, (2) —CR^(e)R^(f)═, (3) —N(R⁷)═,and (4) —(C═O)═.
 9. A compound of any claim 1, or a pharmaceuticallyacceptable salt thereof, wherein E^(a), E^(b), and E^(c) are eachindependently selected from: (1) —C(R⁵)═, and (2) —N═.
 10. A compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein G¹ isselected from: (1) a bond, and (2) —CR^(e)R^(f)—; G² is selected from:(1) a bond, (2) —CR^(e)R^(f)—, (3) —C(R^(i))═C(R^(j))—, and (4) —C≡C—;G³ is selected from: (1) a bond, (2) —CR^(e)R^(f)—, (3)—C(R^(i))═C(R^(j))—, (4) —C≡C—, and (5) —(C═O)—; and G⁴ is selectedfrom: (1) —CR^(e)R^(f)—, (2) —N(R⁷)—, (3) —O—, (4) —S(O)_(q)—, (5)—C(R^(i))═C(R^(j))—, and (6) —C≡C—.
 11. A compound of any claim 1, or apharmaceutically acceptable salt thereof, wherein R⁵ is selected from:(1) hydrogen, (2) —CF₃, and (3) halo.
 12. A compound of any of claim 1,pharmaceutically acceptable salt thereof, wherein R⁶ is phenyl orpyridyl.
 13. A compound of any of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R⁷ is hydrogen or methyl.
 14. Acompound of claim 1, wherein the compound of formula (I) is a compoundof formula IA:

wherein A², A⁴, B, E^(a), E^(b), E^(c), G¹, G², G³, G⁴, and R⁶ aredefined herein; and pharmaceutically acceptable salts thereof andindividual enantiomers and diastereomers thereof.
 15. A compound ofclaim 1, wherein the compound of formula (I) is a compound of formulaIB:

wherein B, E^(a), E^(b), E^(c), G¹, G², R⁶, and R⁷ are defined herein;and pharmaceutically acceptable salts thereof and individual enantiomersand diastereomers thereof.
 16. A compound of claim 1, wherein thecompound of formula (I) is a compound of formula IC:

wherein B, E^(a), E^(b), E^(c), R⁶, and R⁷ are defined herein; andpharmaceutically acceptable salts thereof and individual enantiomers anddiastereomers thereof.
 17. A compound of claim 1, wherein the compoundof formula (I) is a compound of formula ID:

wherein B and R⁶ are defined herein; and pharmaceutically acceptablesalts thereof and individual enantiomers and diastereomers thereof. 18.A compound of claim 1, which is selected from the group consisting of(±)N-(5-oxo-2-phenyl-1,1′,3′,5-tetrahydrospiro[imidazole-4,2′-inden]-5′-yl)-2-[2-oxo-3-(1,3-thiazol-2-yl)-2,3-dihydro-1H-benzimidazol-1-yl]acetamide;(±)-2-(2-oxo-3-pyridin-2-yl-2,3-dihydro-1H-benzimidazol-1-yl)-N-(5-oxo-2-pyridin-2-yl-1,1′,3′,5-tetrahydrospiro[imidazole-4,2′-inden]-5′-yl)acetamide;or a pharmaceutically acceptable salt thereof.
 19. A compound of claim1, which is selected from the group consisting of

or a pharmaceutically acceptable salt thereof.
 20. A pharmaceuticalcomposition which comprises a pharmaceutically acceptable carrier and acompound of claim 1, or a pharmaceutically acceptable salt thereof. 21.A method for treating headache in a mammalian patient in need thereof,which comprises administering to the patient a therapeutically effectiveamount of a compound of claim 1, or a pharmaceutically acceptable saltthereof.
 22. (canceled)